Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

The molecular basis for sugar import in malaria parasites


Elucidating the mechanism of sugar import requires a molecular understanding of how transporters couple sugar binding and gating events. Whereas mammalian glucose transporters (GLUTs) are specialists1, the hexose transporter from the malaria parasite Plasmodium falciparum PfHT12,3 has acquired the ability to transport both glucose and fructose sugars as efficiently as the dedicated glucose (GLUT3) and fructose (GLUT5) transporters. Here, to establish the molecular basis of sugar promiscuity in malaria parasites, we determined the crystal structure of PfHT1 in complex with d-glucose at a resolution of 3.6 Å. We found that the sugar-binding site in PfHT1 is very similar to those of the distantly related GLUT3 and GLUT5 structures4,5. Nevertheless, engineered PfHT1 mutations made to match GLUT sugar-binding sites did not shift sugar preferences. The extracellular substrate-gating helix TM7b in PfHT1 was positioned in a fully occluded conformation, providing a unique glimpse into how sugar binding and gating are coupled. We determined that polar contacts between TM7b and TM1 (located about 15 Å from d-glucose) are just as critical for transport as the residues that directly coordinate d-glucose, which demonstrates a strong allosteric coupling between sugar binding and gating. We conclude that PfHT1 has achieved substrate promiscuity not by modifying its sugar-binding site, but instead by evolving substrate-gating dynamics.

This is a preview of subscription content, access via your institution

Access options

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: PfHT1 in d-glucose-bound occluded conformation.
Fig. 2: Molecular recognition of d-glucose by PfHT1.
Fig. 3: Gating helix in PfHT1 enables substrate promiscuity.
Fig. 4: The conformational-selection-driven rocker-switch mechanism for facilitative sugar transport.

Similar content being viewed by others

Data availability

The coordinates and the structure factors for PfHT1 have been deposited in the PDB 6RW3. All data are available in the paper or Supplementary Information.


  1. Mueckler, M. & Thorens, B. The SLC2 (GLUT) family of membrane transporters. Mol. Aspects Med. 34, 121–138 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Woodrow, C. J., Penny, J. I. & Krishna, S. Intraerythrocytic Plasmodium falciparum expresses a high affinity facilitative hexose transporter. J. Biol. Chem. 274, 7272–7277 (1999).

    CAS  PubMed  Google Scholar 

  3. Woodrow, C. J., Burchmore, R. J. & Krishna, S. Hexose permeation pathways in Plasmodium falciparum-infected erythrocytes. Proc. Natl Acad. Sci. USA 97, 9931–9936 (2000).

    ADS  CAS  PubMed  Google Scholar 

  4. Deng, D. et al. Molecular basis of ligand recognition and transport by glucose transporters. Nature 526, 391–396 (2015).

    ADS  CAS  PubMed  Google Scholar 

  5. Nomura, N. et al. Structure and mechanism of the mammalian fructose transporter GLUT5. Nature 526, 397–401 (2015).

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  6. Kirk, K., Horner, H. A. & Kirk, J. Glucose uptake in Plasmodium falciparum-infected erythrocytes is an equilibrative not an active process. Mol. Biochem. Parasitol. 82, 195–205 (1996).

    CAS  PubMed  Google Scholar 

  7. Roth, E. Jr. Plasmodium falciparum carbohydrate metabolism: a connection between host cell and parasite. Blood Cells 16, 453–460, 461–466 (1990).

    CAS  PubMed  Google Scholar 

  8. Joet, T., Eckstein-Ludwig, U., Morin, C. & Krishna, S. Validation of the hexose transporter of Plasmodium falciparum as a novel drug target. Proc. Natl Acad. Sci. USA 100, 7476–7479 (2003).

    ADS  CAS  PubMed  Google Scholar 

  9. Dean, P., Major, P., Nakjang, S., Hirt, R. P. & Embley, T. M. Transport proteins of parasitic protists and their role in nutrient salvage. Front Plant Sci 5, 153 (2014).

    PubMed  PubMed Central  Google Scholar 

  10. Ortiz, D. et al. Identification of selective inhibitors of the Plasmodium falciparum hexose transporter PfHT by screening focused libraries of anti-malarial compounds. PLoS ONE 10, e0123598 (2015).

    PubMed  PubMed Central  Google Scholar 

  11. Krishna, S. et al. Transport processes in Plasmodium falciparum-infected erythrocytes: potential as new drug targets. Int. J. Parasitol. 32, 1567–1573 (2002).

    CAS  PubMed  Google Scholar 

  12. Yan, N. Structural advances for the major facilitator superfamily (MFS) transporters. Trends Biochem. Sci. 38, 151–159 (2013).

    CAS  PubMed  Google Scholar 

  13. Madej, M. G., Sun, L., Yan, N. & Kaback, H. R. Functional architecture of MFS d-glucose transporters. Proc. Natl Acad. Sci. USA 111, E719–E727 (2014).

    ADS  CAS  PubMed  Google Scholar 

  14. Abramson, J. et al. Structure and mechanism of the lactose permease of Escherichia coli. Science 301, 610–615 (2003).

    ADS  CAS  PubMed  Google Scholar 

  15. Maiden, M. C., Davis, E. O., Baldwin, S. A., Moore, D. C. & Henderson, P. J. Mammalian and bacterial sugar transport proteins are homologous. Nature 325, 641–643 (1987).

    ADS  CAS  PubMed  Google Scholar 

  16. Pao, S. S., Paulsen, I. T. & Saier, M. H. Jr. Major facilitator superfamily. Microbiol. Mol. Biol. Rev. 62, 1–34 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Blume, M. et al. A constitutive pan-hexose permease for the Plasmodium life cycle and transgenic models for screening of antimalarial sugar analogs. FASEB J. 25, 1218–1229 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Deng, D. et al. Crystal structure of the human glucose transporter GLUT1. Nature 510, 121–125 (2014).

    ADS  CAS  PubMed  Google Scholar 

  19. Sun, L. et al. Crystal structure of a bacterial homologue of glucose transporters GLUT1–4. Nature 490, 361–366 (2012).

    ADS  CAS  PubMed  Google Scholar 

  20. Quistgaard, E. M., Löw, C., Moberg, P., Trésaugues, L. & Nordlund, P. Structural basis for substrate transport in the GLUT-homology family of monosaccharide transporters. Nat. Struct. Mol. Biol. 20, 766–768 (2013).

    CAS  PubMed  Google Scholar 

  21. Wisedchaisri, G., Park, M. S., Iadanza, M. G., Zheng, H. & Gonen, T. Proton-coupled sugar transport in the prototypical major facilitator superfamily protein XylE. Nat. Commun. 5, 4521 (2014).

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  22. Drew, D. & Boudker, O. Shared molecular mechanisms of membrane transporters. Annu. Rev. Biochem. 85, 543–572 (2016).

    CAS  PubMed  Google Scholar 

  23. Yan, N. A glimpse of membrane transport through structures–advances in the structural biology of the GLUT glucose transporters. J. Mol. Biol. 429, 2710–2725 (2017).

    CAS  PubMed  Google Scholar 

  24. Uldry, M., Ibberson, M., Hosokawa, M. & Thorens, B. GLUT2 is a high affinity glucosamine transporter. FEBS Lett. 524, 199–203 (2002).

    CAS  PubMed  Google Scholar 

  25. Majd, H. et al. Screening of candidate substrates and coupling ions of transporters by thermostability shift assays. eLife 7, e38821 (2018).

    PubMed  PubMed Central  Google Scholar 

  26. Colville, C. A., Seatter, M. J., Jess, T. J., Gould, G. W. & Thomas, H. M. Kinetic analysis of the liver-type (GLUT2) and brain-type (GLUT3) glucose transporters in Xenopus oocytes: substrate specificities and effects of transport inhibitors. Biochem. J. 290, 701–706 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Burant, C. F., Takeda, J., Brot-Laroche, E., Bell, G. I. & Davidson, N. O. Fructose transporter in human spermatozoa and small intestine is GLUT5. J. Biol. Chem. 267, 14523–14526 (1992).

    CAS  PubMed  Google Scholar 

  28. Hresko, R. C., Kraft, T. E., Quigley, A., Carpenter, E. P. & Hruz, P. W. Mammalian glucose transporter activity is dependent upon anionic and conical phospholipids. J. Biol. Chem. 291, 17271–17282 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Holman, G. D. Chemical biology probes of mammalian GLUT structure and function. Biochem. J. 475, 3511–3534 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Kraft, T. E. et al. A novel fluorescence resonance energy transfer-based screen in high-throughput format to identify inhibitors of malarial and human glucose transporters. Antimicrob. Agents Chemother. 60, 7407–7414 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Seatter, M. J., De la Rue, S. A., Porter, L. M. & Gould, G. W. QLS motif in transmembrane helix VII of the glucose transporter family interacts with the C-1 position of d-glucose and is involved in substrate selection at the exofacial binding site. Biochemistry 37, 1322–1326 (1998).

    CAS  PubMed  Google Scholar 

  32. Manolescu, A., Salas-Burgos, A. M., Fischbarg, J. & Cheeseman, C. I. Identification of a hydrophobic residue as a key determinant of fructose transport by the facilitative hexose transporter SLC2A7 (GLUT7). J. Biol. Chem. 280, 42978–42983 (2005).

    CAS  PubMed  Google Scholar 

  33. Kota, J., Gilstring, C. F. & Ljungdahl, P. O. Membrane chaperone Shr3 assists in folding amino acid permeases preventing precocious ERAD. J. Cell Biol. 176, 617–628 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Drew, D. et al. GFP-based optimization scheme for the overexpression and purification of eukaryotic membrane proteins in Saccharomyces cerevisiae. Nat. Protoc. 3, 784–798 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Kawate, T. & Gouaux, E. Fluorescence-detection size-exclusion chromatography for precrystallization screening of integral membrane proteins. Structure 14, 673–681 (2006).

    CAS  PubMed  Google Scholar 

  36. Kabsch, W. XDS. Acta Crystallogr. D 66, 125–132 (2010).

    CAS  PubMed  Google Scholar 

  37. Evans, P. R. An introduction to data reduction: space-group determination, scaling and intensity statistics. Acta Crystallogr. D 67, 282–292 (2011).

    CAS  PubMed  Google Scholar 

  38. Afonine, P. V. et al. Towards automated crystallographic structure refinement with phenix.refine. Acta Crystallogr. D 68, 352–367 (2012).

    CAS  PubMed  Google Scholar 

  39. DiMaio, F. et al. Improved low-resolution crystallographic refinement with Phenix and Rosetta. Nat. Methods 10, 1102–1104 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Adams, P. D. et al. PHENIX: a comprehensive Python-based system for macromolecular structure solution. Acta Crystallogr. D 66, 213–221 (2010).

    Google Scholar 

  41. Headd, J. J. et al. Use of knowledge-based restraints in phenix.refine to improve macromolecular refinement at low resolution. Acta Crystallogr. D 68, 381–390 (2012).

    CAS  PubMed  Google Scholar 

  42. Smart, O. S. et al. Exploiting structure similarity in refinement: automated NCS and target-structure restraints in BUSTER. Acta Crystallogr. D 68, 368–380 (2012).

    CAS  PubMed  Google Scholar 

  43. Emsley, P. & Cowtan, K. Coot: model-building tools for molecular graphics. Acta Crystallogr. D 60, 2126–2132 (2004).

    Google Scholar 

  44. Šali, A. & Blundell, T. L. Comparative protein modelling by satisfaction of spatial restraints. J. Mol. Biol. 234, 779–815 (1993).

    PubMed  Google Scholar 

  45. Jo, S., Kim, T., Iyer, V. G. & Im, W. CHARMM-GUI: a web-based graphical user interface for CHARMM. J. Comput. Chem. 29, 1859–1865 (2008).

    CAS  Google Scholar 

  46. Berendsen, H. J. C., Postma, J. P. M., van Gunsteren, W. F., DiNola, A. & Haak, J. R. Molecular dynamics with coupling to an external bath. J. Chem. Phys. 81, 3684 (1984).

    ADS  CAS  Google Scholar 

  47. Hess, B. P-LINCS: A parallel linear constraint solver for molecular simulation. J. Chem. Theory Comput. 4, 116–122 (2008).

    CAS  PubMed  Google Scholar 

  48. Darden, T., Darrin, Y. & Pedersen, L. Particle mesh Ewald: An Nlog(N) method for Ewald sums in large systems. J. Chem. Phys. 98, 10089–10092 (1993).

    ADS  CAS  Google Scholar 

  49. Abraham, M. J. et al. GROMACS: high performance molecular simulations through multi-level parallelism from laptops to supercomputers. SoftwareX 1–2, 19–25 (2015).

    ADS  Google Scholar 

  50. van der Walt, S. Colbert, S. C. & Varoquaux, G. The NumPy array: a structure for efficient numerical computation. Comput. Sci. Eng. 13, 22 (2011).

    Google Scholar 

  51. Jolliffe, I. T. & Cadima, J. Principal component analysis: a review and recent developments. Philos. Trans. A Math. Phys. Eng. Sci. 374, 20150202 (2016).

    ADS  MathSciNet  PubMed  PubMed Central  MATH  Google Scholar 

  52. Orellana, L., Yoluk, O., Carrillo, O., Orozco, M. & Lindahl, E. Prediction and validation of protein intermediate states from structurally rich ensembles and coarse-grained simulations. Nat. Commun. 7, 12575 (2016).

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  53. Orellana, L., Gustavsson, J., Bergh, C., Yoluk, O. & Lindahl, E. eBDIMS server: protein transition pathways with ensemble analysis in 2D-motion spaces. Bioinformatics 35, 3505–3507 (2019).

    PubMed  PubMed Central  Google Scholar 

Download references


We thank D. Daley for advice on PfHT1 overexpression optimization, and G. von Heijne and S. Newstead for critical reading of the manuscript. X-ray diffraction data were collected at the European Synchrotron Radiation Facility beamlines, the Diamond Light Source beamlines and the MaxIV BioMax beamline with assistance from beamline scientists. This work was funded by the Knut and Alice Wallenberg Foundation (D.D.) and, the Science for Life Laboratory (L.D.); D.D. acknowledges support from EMBO through the Young Investigator Program (YIP).

Author information

Authors and Affiliations



D.D. designed the project. Cloning, expression screening and crystallization of PfHT1 were carried out by A.A.Q. Data collection, structure determination and refinement of PfHT1 were carried out by A.A.Q., E.N., J.B., R.M., M.C. and D.D. Experiments for functional analysis were carried out by A.A.Q. and A.S. Molecular dynamics simulations of PfHT1 were carried out by S.E.M. and L.D. Sugar porter PCA was carried out by L.O. The manuscript was prepared by D.D. with contributions from all authors.

Corresponding author

Correspondence to David Drew.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Peer review information Nature thanks Jeff Abramson and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Extended data figures and tables

Extended Data Fig. 1 PfHT1 is distantly related to both the human GLUT transporters and the bacterial homologue XylE.

a, Unrooted phylogenetic tree of human GLUT1, GLUT2, GLUT3, GLUT4 and GLUT5 (GLUT1–5), rat GLUT5, E. coli XylE and PfHT1 b, Table of protein sequence identity of proteins shown in a. (only rat (and not human) GLUT5 is shown). c, Sequence alignment of PfHT1, human GLUT1–5, rat GLUT5 and E. coli XylE. Secondary structure elements of PfHT1 are indicated above the alignment, and coloured as in Fig. 1c. Residues conserved in at least 80% of the alignment are highlighted by red boxes, and gating residues are highlighted by blue boxes. Conserved binding-site residues between PfHT1 and human GLUT3 are indicated with purple filled dots and non-conserved residues are indicated with non-filled purple dots. Conserved residues close to the binding site are indicated with yellow filled dots and non-conserved residues with non-filled yellow dots. Black bars beneath the alignment indicate residues in the sugar-porter motifs15,16. The Uniprot reference numbers of the alignment proteins are: PfHT1 (Q7KWJ5), human GLUT1 (P11166), human GLUT2 (Q102R8), human GLUT3 (P11169), human GLUT4 (P14672), human GLUT5 (P22732), rat GLUT5 (P43427) and XylE (P0AGF4). For the sake of clarity, residues 109–121 from XylE and residues 54–86 from human GLUT2 were omitted.

Extended Data Fig. 2 PfHT1 has evolved to be an efficient polyspecific sugar transporter.

a, Size-exclusion chromatogram of DDM-purified PfHT1 showing PfHT1 migrates as two oligomeric species (dimer and monomer); the sample migrates as a monomer during SDS–PAGE. b, Time-dependent uptake of [14C]d-mannose (black circles) by PfHT1 in proteoliposomes. Inset, PfHT1 uptake of radiolabelled sugar (cyan trace) compared with non-specific uptake estimated from radioactivity measured from liposomes incubated without protein (black trace). Error bars represent the mean ± s.e.m. of n = 3 biologically independent experiments. c, As in b, for [14C]d-galactose. d, As in b, for [14C]d-fructose. e, As in b, for [3H]d-xylose. f, As in b, for [3H]d-glucosamine.

Extended Data Fig. 3 PfHT1 has evolved to be an efficient polyspecific sugar transporter.

a, Zero trans kinetics of PfHT1 d-glucose transport. Kinetic curves were fitted from data points recorded at increasing d-glucose concentrations after 20 s and fitted by nonlinear regression. Error bars represent mean ± s.e.m. of n = 3 biologically independent experiments. b. As in a, for d-mannose. c, As in a, for d-galactose and except that time points were recorded after 60 s. d, As in a, for d-fructose and except that time points were recorded after 60 s. e, As in a, for d-glucosamine. f, Bars represent specificity constant (kcat/KM) values of PfHT1 for different sugars as tabulated and described in g. g, The fitted values reported for the Michaelis constant (KM) and Vmax of PfHT1 for different transported sugars are mean ± s.e.m. of n = 3 biologically independent experiments. Turnover (kcat) and specificity constant (kcat/KM) values are derived from these kinetic parameters and adjusted to the amount of protein reconstituted into liposomes (Methods).

Extended Data Fig. 4 Overall structural features of the PfHT1 structure.

a, PfHT1 crystallized as a dimer with four molecules in the asymmetric unit. The shared dimer interface was formed between the respective N-terminal domains (blue) that—although not extensive (522 Å buried surface area)—are consistent with the fact that a fraction of purified PfHT1 migrates as a dimer by size-exclusion chromatography (Extended Data Fig. 2a). Notably, the gating helix TM7b is not making any crystal contacts. b, Superposition of the outward-occluded GLUT3 (PDB 4ZWB) (grey) and the occluded PfHT1 structures. The r.m.s.d. is 1.4 Å for 446 pairs of Cα atoms (Methods). c, Cartoon representation of PfHT1 as viewed from the cytoplasm. Blue, NTD; magenta, CTD. ICHs are not shown for clarity. Interdomain salt-bridge-forming residues are shown as sticks, and labelled. d, Cartoon representation of TM7b of human GLUT1 (PDB 4PYP) (orange) and bovine GLUT5 (PDB 4YB9) (purple) in the inward-open conformation, and PfHT1 in the d-glucose-bound (yellow sticks) occluded conformation (magenta). e, Electron density map 2Fo − Fc (1.5σ) (blue mesh) for the PfHT1 structure (left) and the d-glucose residues in the sugar-binding pocket in cyan (right). The Fo – Fc (3.0σ) (green mesh) maps before addition of and refinement in the presence of d-glucose are also shown. Despite the high quality of the maps, we observed no electron density for ICH5 (location in human GLUT3 shown as a dashed ellipse).

Extended Data Fig. 5 Sugars assessed for inhibition of PfHT1.

a, Chemical structures of the investigated sugars used in competitive-uptake assays. Differences in hydroxyl-group position of the respective d-glucose epimers are coloured red. Sugars labelled green were also tested as radiolabelled substrates in time-course experiments (Fig. 1b, Extended Data Fig. 2b–f). b, The competitive uptake of [14C]d-glucose by PfHT1 in proteoliposomes in the absence (white bars) and presence of non-labelled sugars (black bars). Non-specific uptake was estimated from radioactivity measured from liposomes incubated without protein (red bar). Error bars represent mean and s.e.m. of n = 3 biologically independent experiments.

Extended Data Fig. 6 Assessed quality of purified PfHT1–GFP fusions and analysis of the sugar-binding pocket of PfHT1.

a, FSEC traces of DDM-purified PfHT1GFP wild type and mutants of the sugar-binding pocket; PfHT1GFP migrates as two species (dimer and monomer), consistent with purified PfHT1 (Extended Data Fig. 2a). FSEC traces were recorded at least twice for wild type and each respective mutant. b. As in a, for mutants peripheral to the sugar-binding pocket. c, As in a, for mutants located in TM1 and TM7b. d, Cartoon representation of PfHT1 with d-glucose and interacting residues labelled, shown as yellow sticks. The position of d-glucose in E. coli XylE (green) (PDB 4JA3) and d-glucose in human GLUT3 (grey) (PDB 4ZW9) are shown as sticks, after protein superimposition. e, Determination of the Michaelis constant (KM) for d-glucose by the PfHT1 mutant Ala404Glu, constructed to mimic the human GLUT3 binding site. Kinetic curves were fitted from data points recorded over a range of increasing d-glucose concentrations after 90 s, and fitted by nonlinear regression using data from n = 3 biologically independent experiments (values reported are mean ± s.e.m. of the fit). f, As in e, for d-fructose. g, Sugar-binding-site comparison between PfHT1 side chains (yellow sticks) and rat GLUT5 side chains (conserved side chains, grey sticks; non-conserved side chains, cyan sticks). h, As in e, for the PfHT1 mutant Trp412Ala constructed to mimic the rat GLUT5 binding site.

Extended Data Fig. 7 Small-molecule-inhibition analysis of PfHT1.

a, Surface transversal cross-sections through the membrane of the PfHT1 structure in the occluded conformation with d-glucose shown as sticks, and a side vestibule accessible to the C3- and C4-hydoxyl groups that—in human GLUT3—was occupied by a monoolein lipid. b, The competitive uptake of [14C]d-glucose (black bars) by PfHT1 wild type and the mutant W412A in proteoliposomes in the absence and presence of cytochalasin B (Cyb) (120 μM), MMV009085 (MMV) (100 μM) or C3361 (100 μM). Error bars represent s.e.m. of n = 3 biologically independent experiments (left). Cytochalasin B and the inhibitor C3361 (which is d-glucose with a undec-10-en chain at the C3-hydroxyl position) are shown (right). c, IC50 curves for MMV009085 (blue filled circles) and derivative lacking the butanol tails (grey filled circles). Error bars represent s.e.m. of n = 3 biologically independent experiments (left). Structures of MMV009085 and derivative are shown on the right.

Extended Data Fig. 8 The extracellular substrate-gating helix TM7b.

a, Cartoon representation of TM7b of human GLUT3 in the outward-open (green) (PDB 4ZWC) and outward-occluded d-glucose-bound conformation (light-brown) (PDB 4ZW9) and of PfHT1 in the d-glucose-bound occluded conformation (magenta). Arrows indicate that inward movement of TM7b is coupled to coordination of the C3- and C4- hydroxyl groups of d-glucose (shown as yellow sticks) by the strictly conserved asparagine residue corresponding to Asn311 in PfHT1. Only in PfHT1 does TM7b break into two perpendicular segments as observed in the in inward-facing structures of GLUT1 and GLUT5 (Extended Data Fig. 4d). The asterisk highlights the highly conserved tyrosine residues that occlude the substrate from exiting in the outward-occluded conformations, and which—in PfHT1—are replaced by serine (S315) and asparagine (N316). b, Molecular dynamics simulations of TM1–TM7 gating interactions: d-glucose-bound outward-occluded gating interactions by human GLUT3 in the presence (yellow) and absence (grey) of d-glucose. The distribution of conformations, shown as the gating distance, from three independent 1-μs molecular dynamics simulations, as described in the Methods. c, As in b, for d-glucose-bound outward-occluded gating interactions by PfHT1 in the presence (magenta) and absence (yellow) of d-glucose. The distribution of conformations, shown as the gating distance, from three independent 1-μs molecular dynamics simulations, as described in the Methods. d, Snapshots of the distance between residues Lys51 and Asn316 at 0-ns, 500-ns and 1,000-ns time points.

Extended Data Fig. 9 PCA analysis of sugar-porter structure and alternating-access mechanism.

a, Aligned core of near-intact MFS transporter structures from 17 structures, including PfHT1, mammalian (GLUT1, GLUT3 and GLUT5) and prokaryotic (XylE) systems. The ‘core’ structural elements conserved among the structures are shown in different colours (Methods). b, Motions along the first principal component (PC1) derived from the core ensemble, tracking the rocker-switch motion. c, Residue fluctuations computed from PC1, with the core helix fragments shown as shadowed areas at the base. d, Schematic of the structural basis of the sugar-porter alternating-access mechanism. To summarize, in the outward and outward-occluded conformations (PDB 4YBQ and 4ZW9) the substrate-gating helix TM7b (magenta and transparent) is mobile and samples either state, as seen in molecular dynamics simulation of human GLUT3; spontaneous gate closure is further consistent with the fact that—even in the presence of maltose—GLUT3 crystallizes in both outward-open and outward-occluded conformations4. Substrate binding conformationally stabilizes the outward-occluded state, thus increasing the likelihood for TM7b to break in the middle, completely close the substrate pocket and form contacts with TM1. In the occluded state, the salt-bridge interactions between ICH5 in the C-terminal bundle and ICH1, ICH2 ICH3 and ICH4 are lost, which indirectly destabilizes the highly conserved intrabundle salt-bridge network. Breakage of the intrabundle salt-bridge network catalyses global rocker-switch rearrangements of the N- and C-terminal bundles. In the inward-occluded conformation (PDB 4JA3), the intracellular gating helix TM10b (cyan)—which is related by inverted symmetry to TM7b—spontaneously moves outward to the inward-open conformation (PDB 4YB9). After sugar release, the sugar porter spontaneously resets itself to the outward-facing conformation through an ‘empty’ occluded state22. Spontaneous resetting means that the energetic barriers separating opposite-facing states must be low enough that the occluded state can form in the absence of sugar binding. Nevertheless, consistent with a conformational-selection-driven rocker-switch mechanism, substrate binding catalyses transport as rates are substantially faster through ‘substrate-bound’ versus ‘empty’ occluded-state transitions1.

Extended Data Table 1 Zero trans proteoliposome (lacking internal sugar) in vitro kinetics of d-glucose and d-fructose by PfHT1 wild type and mutants
Extended Data Table 2 Data collection and refinement statistics (molecular replacement)

Supplementary information

Supplementary Information

This file contains Supplementary Table 1: Molecular dynamics simulation details of replicates and Supplementary Figure 1: Uncropped gel of Extended Data Fig. 2a.

Reporting Summary

Video 1

Video morphing between the open outward-facing, outward-occluded, occluded, inward-occluded and open inward-facing PfHT1 conformations as viewed parallel to the membrane. The open outward- and inward-facing conformations are based on the GLUT5 structures and occluded states were modelled based on the structures of human GLUT3 and E. coli XylE. (Methods). Morphing between conformations was performed using PyMol.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Qureshi, A.A., Suades, A., Matsuoka, R. et al. The molecular basis for sugar import in malaria parasites. Nature 578, 321–325 (2020).

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:

This article is cited by


By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing