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| Open AccessAn unexpected N-terminal loop in PD-1 dominates binding by nivolumab
Programmed cell death 1 (PD-1) is a key target for cancer immunotherapy. Here the authors present the crystal structure of the extracellular PD-1 domain with the clinically approved monoclonal antibody nivolumab, which shows that the N-terminal PD-1 loop is crucial for antibody binding.
- Shuguang Tan
- , Hao Zhang
- & Jinghua Yan
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Article
| Open AccessPortal protein functions akin to a DNA-sensor that couples genome-packaging to icosahedral capsid maturation
Tailed bacteriophages assemble empty precursor capsids known as procapsids that are subsequently filled with viral DNA by a genome-packaging motor. Here the authors present a structure-based analysis that suggests the signal for termination of genome packaging is achieved through a DNA-dependent symmetrization of portal protein.
- Ravi K. Lokareddy
- , Rajeshwer S. Sankhala
- & Gino Cingolani
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Article
| Open AccessStructural basis for ELL2 and AFF4 activation of HIV-1 proviral transcription
The host super elongation complex (SEC) is hijacked by HIV-1 for viral transcription. Here the authors present the structure of RNA polymerase elongation factor ELL2 bound to the intrinsically disordered scaffold protein AFF4, identifying an ELL2 surface important for HIV-1 transcription.
- Shiqian Qi
- , Zichong Li
- & James H. Hurley
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Article
| Open AccessSec3 promotes the initial binary t-SNARE complex assembly and membrane fusion
Membrane fusion during exocytosis is mediated by interaction between SNARE proteins on vesicles and the cell membrane, but how SNARE complex assembly is initiated remains unknown. Here, the authors show that interaction of Sec3 with Sso2 on the plasma membrane promotes formation of an Sso2–Sec9 complex, an early step in SNARE assembly, likely by inhibiting Sso2 auto-inhibition.
- Peng Yue
- , Yubo Zhang
- & Wei Guo
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Article
| Open AccessHuman farnesyl pyrophosphate synthase is allosterically inhibited by its own product
Farnesyl pyrophosphate (FPP) is a key building block for the synthesis of many lipids. Here the authors determine the crystal structure of farnesyl pyrophosphate synthase (FPPS) with its bound product and use kinetic measurements to show that FPP is an allosteric effector of the enzyme.
- Jaeok Park
- , Michal Zielinski
- & Albert M. Berghuis
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Article
| Open AccessA RuBisCO-mediated carbon metabolic pathway in methanogenic archaea
Although not photosynthetic, some archaea possess RuBisCO, one of the enzymes characteristic of the photosynthetic Calvin-Benson cycle, but apparently lack another one, phosphoribulokinase (PRK). Here the authors describe a carbon metabolic pathway in methanogenic archaea, involving RuBisCO and PRK.
- Takunari Kono
- , Sandhya Mehrotra
- & Hiroki Ashida
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Article
| Open AccessStructural basis for the recognition and degradation of host TRIM proteins by Salmonella effector SopA
The HECT-like E3 ligase SopA inSalmonellahas been suggested to activate host RING ligases TRIM56 and TRIM65. Here, the authors use mass spectrometry, crystal structures and biochemistry to examine the interactions between these proteins in detail.
- Evgenij Fiskin
- , Sagar Bhogaraju
- & Ivan Dikic
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Article
| Open AccessStructure of the cohesin loader Scc2
The cohesin complex maintains genome integrity by ensuring correct sister-chromatid segregation during mitosis and meiosis. Here, Chaoet al. present a pseudo-atomic model of the full-length Scc2–Scc4 cohesin loader complex and reveal key Scc2 surfaces crucial for cohesin loading.
- William C. H. Chao
- , Yasuto Murayama
- & Martin R. Singleton
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Article
| Open AccessStructural and mechanistic basis of proton-coupled metal ion transport in the SLC11/NRAMP family
Cellular uptake of transition metal ions is mediated by members of the SLC11/NRAMP family. Here the authors determine the structural and functional properties of EcoDMT, a bacterial SLC11 transporter, gathering molecular insight into its transport mechanism and proton coupling process.
- Ines A. Ehrnstorfer
- , Cristina Manatschal
- & Raimund Dutzler
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Article
| Open AccessArchitecture and mechanism of the late endosomal Rab7-like Ypt7 guanine nucleotide exchange factor complex Mon1–Ccz1
The Mon1-Ccz1 (MC1) complex is a Rab guanine nucleotide exchange factor (RabGEF) for Ypt7/Rab7 important for endosomal maturation. Here the authors present the biochemical and structural characterization of MC1, elucidating its catalytic mechanism and showing that MC1 represents novel class of RabGEFs.
- Stephan Kiontke
- , Lars Langemeyer
- & Daniel Kümmel
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Article
| Open AccessTransport of lipophilic carboxylates is mediated by transmembrane helix 2 in multidrug transporter AcrB
The AcrB module of the AcrAB-TolC multidrug efflux pump sequesters drugs from the periplasm and outer leaflet of the inner membrane. Here, Oswaldet al. provide evidence that lipophilic carboxylated substrates bind to a groove between transmembrane helices TM1 and TM2, for further transport by an upward movement of TM2.
- Christine Oswald
- , Heng-Keat Tam
- & Klaas M. Pos
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Article
| Open AccessStructural basis of myelin-associated glycoprotein adhesion and signalling
Myelin-associated glycoprotein (MAG) maintains myelin-axon spacing. Here, the authors report the crystal structures of the MAG full ectodomain in complex with oligosaccharide, and use additional assays to provide insights into the mechanism of MAG-mediated signalling.
- Matti F. Pronker
- , Suzanne Lemstra
- & Bert J. C. Janssen
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Article
| Open AccessMembrane pyrophosphatases from Thermotoga maritima and Vigna radiata suggest a conserved coupling mechanism
In some parasites, membrane-bound pyrophosphatases, which couple proton and sodium ion transport across the membrane, are important for infectivity. Here, the authors report crystal structures of these proteins alongside biophysical analyses that allow them to propose a model for how the coupling is achieved.
- Kun-Mou Li
- , Craig Wilkinson
- & Adrian Goldman
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Article
| Open AccessHuman antibody 3E1 targets the HA stem region of H1N1 and H5N6 influenza A viruses
Treatment of influenza A viruses with broadly neutralizing monoclonal antibodies is an area of active research. Here, the authors characterise a human monoclonal antibody called 3E1 that was reactive against both H1 and H5 viruses in vitroand demonstrated some treatment efficacy in mice.
- Wenshuai Wang
- , Xiaoyu Sun
- & Bing Sun
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Article
| Open AccessStructure of the RBM7–ZCCHC8 core of the NEXT complex reveals connections to splicing factors
RBM7 and ZCCHC8 are two core subunits of the Nuclear Exosome Targeting complex, which regulates the degradation of selected non-coding RNAs in human cells. Here, the authors use structural and biochemical methods to show how ZCCHC8 recruits RBM7 in the complex, leaving the RNA binding site accessible and revealing possible implications for splicing.
- Sebastian Falk
- , Ksenia Finogenova
- & Elena Conti
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Article
| Open AccessStructural decoding of netrin-4 reveals a regulatory function towards mature basement membranes
Netrins are secreted guidance factors that promote axon outgrowth and orientation during nervous system development. Here the authors present structural and biological evidence that netrin-4 is not a guidance cue per se, but rather functions to modulate laminin-laminin interactions.
- Raphael Reuten
- , Trushar R. Patel
- & Manuel Koch
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Article
| Open AccessDirect visualization of a Fe(IV)–OH intermediate in a heme enzyme
The nature of the ferryl intermediate generated in reactions catalysed by heme-containing enzymes is uncertain, due to the ambiguity of X-ray crystallography data. Here, the authors apply neutron diffraction, kinetics and other spectroscopy to directly observe a protonated ferryl intermediate in a heme peroxidase.
- Hanna Kwon
- , Jaswir Basran
- & Emma L. Raven
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Article
| Open AccessInteraction of the cotranslational Hsp70 Ssb with ribosomal proteins and rRNA depends on its lid domain
In yeast, the heterodimeric ribosome-associated complex (RAC) acts in concert with the Hsp70 protein Ssb, forming a unique chaperone triad. Here the authors use structural and biochemical approaches to shed light on how translation and folding are coupled in eukaryotes.
- Andrea Gumiero
- , Charlotte Conz
- & Irmgard Sinning
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Article
| Open AccessGermline-encoded neutralization of a Staphylococcus aureus virulence factor by the human antibody repertoire
Staphylococcus aureuscan both cause disease in humans and be present with no discernible effect. Here, the authors look in detail at the memory immune response against a protein involved in iron acquisition.
- Yik Andy Yeung
- , Davide Foletti
- & Javier Chaparro-Riggers
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Article
| Open AccessAn elastic element in the protocadherin-15 tip link of the inner ear
Tip-link filaments convey force to activate hair cells, important sensory receptors. Here the authors solve a partial structure of human protocadherin-15, a tip-link component with an unusual Ca2+–free linker that bends and is predicted to confer flexibility to this filament during inner-ear mechanotransduction.
- Raul Araya-Secchi
- , Brandon L. Neel
- & Marcos Sotomayor
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Article
| Open AccessStructure of the NS2B-NS3 protease from Zika virus after self-cleavage
The proteases of flaviviruses are promising targets for development of specific antiviral drugs. Here, the authors report a high resolution crystal structure of the NS2B-NS3 protease of Zika virus that provides insight into substrate and inhibitor binding.
- Wint Wint Phoo
- , Yan Li
- & Dahai Luo
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Article
| Open AccessReader domain specificity and lysine demethylase-4 family function
KDM4 histone demethylases target specific chromatin regions by a mechanism that is not fully characterised. Here, the authors identify trimethyl-lysine histone-binding preferences for closely related KDM4 double tudor domains and use structural and biochemical information to examine the molecular details of this interaction.
- Zhangli Su
- , Fengbin Wang
- & John M. Denu
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Article
| Open AccessCoupled binding mechanism of three sodium ions and aspartate in the glutamate transporter homologue GltTk
In neurons and glia, glutamate transporters catalyse the reuptake of this neurotransmitter by coupling it with cation transport. Here the authors combine X-ray crystallography and molecular dynamics simulations of the archeal glutamate transporter GltTkto get insight into the coupled transport mechanism.
- Albert Guskov
- , Sonja Jensen
- & Dirk Jan Slotboom
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Article
| Open AccessCrystal structure of bacterial haem importer complex in the inward-facing conformation
Pathogenic bacteria acquire iron from heme cofactors imported by ABC heme transporters. Here the authors present crystal structures of Burkholderia cenocepaciaheme importer BhuUV with and without the heme-binding protein BhuT, gathering mechanistic insight into the catalytic cycle of heme import.
- Youichi Naoe
- , Nozomi Nakamura
- & Hiroshi Sugimoto
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Article
| Open AccessStructural and mechanistic insights into regulation of the retromer coat by TBC1d5
Retromer is recruited to endosomes by the small GTPase Rab7 and sorting nexin 3. Here, the authors report the interaction between a GTPase-activating protein TBC1d5 and Rab7, examine the biochemical details of the interaction with retromer, and discuss the implications for receptor trafficking.
- Da Jia
- , Jin-San Zhang
- & Michael K. Rosen
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Article
| Open AccessStructural basis of GM-CSF and IL-2 sequestration by the viral decoy receptor GIF
Viruses often subvert the host immune system using molecular decoys to prevent an effective immune response. Here, the authors examine the structural details of the viral decoy receptor GIF and its antagnosim of GM-CSF and IL-2.
- Jan Felix
- , Eaazhisai Kandiah
- & Savvas N. Savvides
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Article
| Open AccessSelenium single-wavelength anomalous diffraction de novo phasing using an X-ray-free electron laser
X-ray free electron lasers are increasingly available for use in macromolecular structure determination. Here, the authors describe the successful use of selenium single-wavelength anomalous diffraction data to calculate experimentally derived phases.
- Mark S. Hunter
- , Chun Hong Yoon
- & Sébastien Boutet
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Article
| Open AccessStructure of the bacterial plant-ferredoxin receptor FusA
Many bacteria use TonB-dependent outer membrane receptors to scavenge iron from their host during infection. Here, the authors report on the structure and function of FusA, which is a bacterial receptor that is used to obtain iron from plants.
- Rhys Grinter
- , Inokentijs Josts
- & Daniel Walker
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Article
| Open AccessStructural basis of checkpoint blockade by monoclonal antibodies in cancer immunotherapy
Immunotherapy is offering patients with cancer new therapy options. Here, the authors report on the crystal structures of some of these therapies bound to their targets.
- Ju Yeon Lee
- , Hyun Tae Lee
- & Yong-Seok Heo
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Article
| Open AccessCrystal structures of the ATP-binding and ADP-release dwells of the V1 rotary motor
V1-ATPases are rotary molecular motors that are powered by ATP hydrolysis. Here, the authors report two of the missing rotary states of this protein complex, and perform biochemical analysis to investigate the binding mode of the nucleotides.
- Kano Suzuki
- , Kenji Mizutani
- & Takeshi Murata
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Article
| Open AccessT cell receptor recognition of CD1b presenting a mycobacterial glycolipid
Germline-encoded mycolyl lipid-reactive (GEM) T cells recognize CD1b proteins presenting mycobacterial mycolates via their T-cell receptors (TCRs). Here, the authors present the structure of this interaction and provide a molecular basis for the co-recognition of CD1b and a mycobacterial glycolipid.
- Stephanie Gras
- , Ildiko Van Rhijn
- & Jamie Rossjohn
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Article
| Open AccessQuantitative interaction mapping reveals an extended UBX domain in ASPL that disrupts functional p97 hexamers
The AAA+ ATPase p97 is an essential hexameric protein with multiple protein interaction partners and cellular functions. Here, the authors use interaction mapping to examine partner proteins of this large complex, and assess the effects of these proteins on the disassembly of the p97 complex.
- Anup Arumughan
- , Yvette Roske
- & Erich E. Wanker
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Article
| Open AccessNop9 is a PUF-like protein that prevents premature cleavage to correctly process pre-18S rRNA
Nop9 is a conserved small ribosomal subunit biogenesis factor. Here, Zhang et al. show that Nop9, in complex with RNA, adopts a C-shaped fold formed from 11 Pumillo repeats and propose that Nop9 inhibits premature cleavage of 20S pre-rRNA by inhibiting the Nob1 nuclease.
- Jun Zhang
- , Kathleen L. McCann
- & Traci M. Tanaka Hall
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Article
| Open AccessHuman acid sphingomyelinase structures provide insight to molecular basis of Niemann–Pick disease
Genetic alterations in the protein acid sphingomyelinase (ASM) lead to ASM deficiency and have been associated with Niemann–Pick disease. Here, the authors report the crystal structures of ASM alone and bound to its product, and discuss the catalytic mechanism and its possible significance for patients with ASM deficiency.
- Yan-Feng Zhou
- , Matthew C. Metcalf
- & Ronnie R. Wei
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Article
| Open AccessStructural characterization of antibiotic self-immunity tRNA synthetase in plant tumour biocontrol agent
The bacterium Agrobacterium radiobacter K84 secretes an antibiotic that is transported into the plant pathogen A. tumefaciensand processed into the toxin TM84. Here, the authors identify a mechanism whereby the antibiotic-producing microbe resists its own toxin.
- Shaileja Chopra
- , Andrés Palencia
- & John Reader
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Article
| Open AccessA distinct holoenzyme organization for two-subunit pyruvate carboxylase
Pyruvate carboxylases are homotetrameric enzymes in eukaryotes and most bacteria. Here, the authors report the structure of an unusual two-subunit form of the enzyme from the Gram-negative bacterium Methylobacillus flagellates, revealing an unexpected α2β4stoichiometry.
- Philip H. Choi
- , Jeanyoung Jo
- & Liang Tong
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Article
| Open AccessCrystal structures of the human elongation factor eEFSec suggest a non-canonical mechanism for selenocysteine incorporation
Specialized translation elongation factors (eEFSec and SelB) promote selenocysteine incorporation into proteins. Here, the authors report the structure of human eEFSec, examine its interactions with guanine nucleotides, and propose a non-canonical mechanism for decoding selenocysteine.
- Malgorzata Dobosz-Bartoszek
- , Mark H. Pinkerton
- & Miljan Simonović
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Article
| Open AccessStructural and functional characterization of a calcium-activated cation channel from Tsukamurella paurometabola
Tetrameric cationic channels specificity is determined by the sequence and structural conformation of their selectivity filter. Here, the authors show that a cationic channel from Tsukamurella paurometabola is non-selective due to a Ca2+-binding motif within its unusual proline-rich filter.
- Balasundaresan Dhakshnamoorthy
- , Ahmed Rohaim
- & Benoît Roux
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Article
| Open AccessThe structural basis for CD36 binding by the malaria parasite
Targeting of the CD36 scavenger receptor by the malaria parasite effector PfEMP1 prevents splenic clearance of infected erythrocytes. Here, the authors propose that diverse PfEMP1 achieve this by binding to a conserved phenylalanine residue in CD36 that is also required for lipoprotein binding.
- Fu-Lien Hsieh
- , Louise Turner
- & Matthew K. Higgins
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Article
| Open AccessStructural insights into the interaction and disease mechanism of neurodegenerative disease-associated optineurin and TBK1 proteins
Mutations in optineurin that cause defects in the interaction with TBK1 are associated with neurodegenerative diseases. Here, the authors report the structure of this complex, and outline a general binding mode for these proteins.
- Faxiang Li
- , Xingqiao Xie
- & Lifeng Pan
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Article
| Open AccessStructural basis underlying viral hijacking of a histone chaperone complex
The Epstein-Barr virus tegument protein BNRF1 is required for the establishment of selective viral gene expression during latency and interacts with the histone chaperone DAXX. Here the authors provide structural insight into how BNRF1 hijacks the DAXX-histone H3.3-H4 complex.
- Hongda Huang
- , Zhong Deng
- & Dinshaw J. Patel
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Article
| Open AccessIdentification of KasA as the cellular target of an anti-tubercular scaffold
Screens for bactericidal compounds have resulted in promising anti-tubercular hits. Here, the authors analyse in detail the target of an indazole sulfonamide (GSK3011724A), and find that it has a different mode of inhibition compared to other Kas inhibitors of fatty acid biosynthesis in bacteria.
- Katherine A. Abrahams
- , Chun-wa Chung
- & Robert H. Bates
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Article
| Open AccessThe myosin X motor is optimized for movement on actin bundles
Myosin X is a molecular motor unique in its ability to generate filopodia, but the mechanism explaining this behaviour is not known. Here, through a combination of structure, single-molecule assays and modelling the authors show that myosin X is optimized for transport along actin bundles.
- Virginie Ropars
- , Zhaohui Yang
- & Anne Houdusse
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Article
| Open AccessNucleotide binding by the widespread high-affinity cyclic di-GMP receptor MshEN domain
Cyclic-di-GMP is a bacterial second messenger that binds to the regulatory domain of ATPases of some bacteria. Here, the authors report the crystal structure of this interaction, identify a cyclic-di-GMP binding mode, and show that this interaction might be important for bacterial biofilm formation.
- Yu-Chuan Wang
- , Ko-Hsin Chin
- & Shan-Ho Chou
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Article
| Open AccessCrystal structure and functional characterization of a light-driven chloride pump having an NTQ motif
The atypical rhodopsin ClR from flavobacterium Nonlabens marinusis a light-driven chloride-pumping protein. Here, the authors show that ClR crystal structure presents two chloride ion-binding sites, proposing a molecular pathway for ion transport by this light-driven pump.
- Kuglae Kim
- , Soon-Kyeong Kwon
- & Hyun-Soo Cho
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Article
| Open AccessLinear ubiquitination is involved in the pathogenesis of optineurin-associated amyotrophic lateral sclerosis
Mutations in optineurin are associated with neurodegenerative diseases, including amyotrophic lateral sclerosis. Here, the authors report the structure of the ubiquitin binding domain of optineurin, which binds linear ubiquitin with homology to NEMO, and explore the function of this domain.
- Seshiru Nakazawa
- , Daisuke Oikawa
- & Fuminori Tokunaga
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Article
| Open AccessA MUB E2 structure reveals E1 selectivity between cognate ubiquitin E2s in eukaryotes
Regulators of the important ubiquitylation cascade are not well studied. Here, the authors report the crystal structure of a prenylated membrane-anchored ubiquitin-fold protein from Arabidopsisbound to an E2 protein and conclude that it is an example of selective activation between E2 enzymes.
- Xiaolong Lu
- , Konstantin R. Malley
- & Brian P. Downes
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Article
| Open AccessLipidic cubic phase injector is a viable crystal delivery system for time-resolved serial crystallography
Serial femtosecond crystallography using X-ray free-electron lasers has huge potential for time-resolved structural experiments. Here, the authors present a structure of the light-driven proton pump bacteriorhodopsin using these techniques.
- Przemyslaw Nogly
- , Valerie Panneels
- & Jörg Standfuss
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Article
| Open AccessCrystal structure of the plant receptor-like kinase TDR in complex with the TDIF peptide
The TDF peptide interacts with the leucine-rich repeat receptor-like kinase TDR to regulate meristem differentiation in plants. Here, the authors solve the structure of the extracellular domain of TDR in complex with TDIF and propose a mechanism for TDIF recognition.
- Junko Morita
- , Kazuki Kato
- & Osamu Nureki