Chemokines and their receptors mediate cell migration, which influences multiple fundamental biological processes and disease conditions such as inflammation and cancer1. Although ample effort has been invested into the structural investigation of the chemokine receptors and receptor–chemokine recognition2,3,4, less is known about endogenous chemokine-induced receptor activation and G-protein coupling. Here we present the cryo-electron microscopy structures of interleukin-8 (IL-8, also known as CXCL8)-activated human CXC chemokine receptor 2 (CXCR2) in complex with Gi protein, along with a crystal structure of CXCR2 bound to a designed allosteric antagonist. Our results reveal a unique shallow mode of binding between CXCL8 and CXCR2, and also show the interactions between CXCR2 and Gi protein. Further structural analysis of the inactive and active states of CXCR2 reveals a distinct activation process and the competitive small-molecule antagonism of chemokine receptors. In addition, our results provide insights into how a G-protein-coupled receptor is activated by an endogenous protein molecule, which will assist in the rational development of therapeutics that target the chemokine system for better pharmacological profiles.
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The atomic coordinates for CXCR2–CXCL8 monomer–Gi–scFv16, CXCR2–CXCL8 dimer–Gi–scFv16 and CXCR2–00767013 have been deposited in the Protein Data Bank (PDB) with the accession codes 6LFO, 6LFM and 6LFL, respectively. The electron microscopy maps for CXCR2–CXCL8 monomer–Gi–scFv16 and CXCR2–CXCL8 dimer–Gi–scFv16 have been deposited in the Electron Microscopy Data Bank (EMDB) with the accession codes EMD-0879 and EMD-0877, respectively. All other data are available upon request from the corresponding authors.
Le, Y., Zhou, Y., Iribarren, P. & Wang, J. Chemokines and chemokine receptors: their manifold roles in homeostasis and disease. Cell. Mol. Immunol. 1, 95–104 (2004).
Qin, L. et al. Structural biology. Crystal structure of the chemokine receptor CXCR4 in complex with a viral chemokine. Science 347, 1117–1122 (2015).
Burg, J. S. et al. Structural biology. Structural basis for chemokine recognition and activation of a viral G protein-coupled receptor. Science 347, 1113–1117 (2015).
Zheng, Y. et al. Structure of CC chemokine receptor 5 with a potent chemokine antagonist reveals mechanisms of chemokine recognition and molecular mimicry by HIV. Immunity 46, 1005–1017 (2017).
Zhu, Y. M., Webster, S. J., Flower, D. & Woll, P. J. Interleukin-8/CXCL8 is a growth factor for human lung cancer cells. Br. J. Cancer 91, 1970–1976 (2004).
Murphy, P. M. & Tiffany, H. L. Cloning of complementary DNA encoding a functional human interleukin-8 receptor. Science 253, 1280–1283 (1991).
Waugh, D. J. & Wilson, C. The interleukin-8 pathway in cancer. Clin. Cancer Res. 14, 6735–6741 (2008).
Ning, Y. et al. Interleukin-8 is associated with proliferation, migration, angiogenesis and chemosensitivity in vitro and in vivo in colon cancer cell line models. Int. J. Cancer 128, 2038–2049 (2011).
Bizzarri, C. et al. ELR+ CXC chemokines and their receptors (CXC chemokine receptor 1 and CXC chemokine receptor 2) as new therapeutic targets. Pharmacol. Ther. 112, 139–149 (2006).
Nasser, M. W. et al. Differential activation and regulation of CXCR1 and CXCR2 by CXCL8 monomer and dimer. J. Immunol. 183, 3425–3432 (2009).
Das, S. T. et al. Monomeric and dimeric CXCL8 are both essential for in vivo neutrophil recruitment. PLoS ONE 5, e11754 (2010).
Cheng, Y., Ma, X. L., Wei, Y. Q. & Wei, X. W. Potential roles and targeted therapy of the CXCLs/CXCR2 axis in cancer and inflammatory diseases. Biochim. Biophys. Acta Rev. Cancer 1871, 289–312 (2019).
Wu, B. et al. Structures of the CXCR4 chemokine GPCR with small-molecule and cyclic peptide antagonists. Science 330, 1066–1071 (2010).
Tan, Q. et al. Structure of the CCR5 chemokine receptor-HIV entry inhibitor maraviroc complex. Science 341, 1387–1390 (2013).
Oswald, C. et al. Intracellular allosteric antagonism of the CCR9 receptor. Nature 540, 462–465 (2016).
Zheng, Y. et al. Structure of CC chemokine receptor 2 with orthosteric and allosteric antagonists. Nature 540, 458–461 (2016).
Jaeger, K. et al. Structural basis for allosteric ligand recognition in the human CC chemokine receptor 7. Cell 178, 1222–1230 (2019).
Lowman, H. B. et al. Monomeric variants of IL-8: effects of side chain substitutions and solution conditions upon dimer formation. Protein Sci. 6, 598–608 (1997).
Berkamp, S., Park, S. H., De Angelis, A. A., Marassi, F. M. & Opella, S. J. Structure of monomeric interleukin-8 and its interactions with the N-terminal binding site-I of CXCR1 by solution NMR spectroscopy. J. Biomol. NMR 69, 111–121 (2017).
Ravindran, A., Sawant, K. V., Sarmiento, J., Navarro, J. & Rajarathnam, K. Chemokine CXCL1 dimer is a potent agonist for the CXCR2 receptor. J. Biol. Chem. 288, 12244–12252 (2013).
Koehl, A. et al. Structure of the µ-opioid receptor-Gi protein complex. Nature 558, 547–552 (2018).
García-Nafría, J., Nehmé, R., Edwards, P. C. & Tate, C. G. Cryo-EM structure of the serotonin 5-HT1B receptor coupled to heterotrimeric Go. Nature 558, 620–623 (2018).
Draper-Joyce, C. J. et al. Structure of the adenosine-bound human adenosine A1 receptor-Gi complex. Nature 558, 559–563 (2018).
Maeda, S., Qu, Q., Robertson, M. J., Skiniotis, G. & Kobilka, B. K. Structures of the M1 and M2 muscarinic acetylcholine receptor/G-protein complexes. Science 364, 552–557 (2019).
Scholten, D. J. et al. Pharmacological modulation of chemokine receptor function. Br. J. Pharmacol. 165, 1617–1643 (2012).
Prado, G. N. et al. Chemokine signaling specificity: essential role for the N-terminal domain of chemokine receptors. Biochemistry 46, 8961–8968 (2007).
Joseph, P. R. et al. Dynamic conformational switching in the chemokine ligand is essential for G-protein-coupled receptor activation. Biochem. J. 456, 241–251 (2013).
Ballesteros, J. A. & Weinstein, H. in Methods in Neurosciences Vol. 25 (ed. Sealfon, S. C.) 366–428 (1995).
Krishna Kumar, K. et al. Structure of a signaling cannabinoid receptor 1-G protein complex. Cell 176, 448–458 (2019).
Hua, T. et al. Activation and signaling mechanism revealed by cannabinoid receptor–Gi complex structures. Cell 180, 655–665 (2020).
Xing, C. et al. Cryo-EM structure of the human cannabinoid receptor CB2–Gi signaling complex. Cell 180, 645–654 (2020).
Rasmussen, S. G. et al. Crystal structure of the β2 adrenergic receptor–Gs protein complex. Nature 477, 549–555 (2011).
Kleist, A. B. et al. New paradigms in chemokine receptor signal transduction: moving beyond the two-site model. Biochem. Pharmacol. 114, 53–68 (2016).
Roumen, L. et al. C(X)CR in silico: computer-aided prediction of chemokine receptor–ligand interactions. Drug Discov. Today. Technol. 9, e281–e291 (2012).
Ngo, T. et al. Crosslinking-guided geometry of a complete CXC receptor–chemokine complex and the basis of chemokine subfamily selectivity. PLoS Biol. 18, e3000656 (2020).
Crump, M. P. et al. Solution structure and basis for functional activity of stromal cell-derived factor-1; dissociation of CXCR4 activation from binding and inhibition of HIV-1. EMBO J. 16, 6996–7007 (1997).
Monteclaro, F. S. & Charo, I. F. The amino-terminal domain of CCR2 is both necessary and sufficient for high affinity binding of monocyte chemoattractant protein 1. Receptor activation by a pseudo-tethered ligand. J. Biol. Chem. 272, 23186–23190 (1997).
Hauser, A. S., Attwood, M. M., Rask-Andersen, M., Schiöth, H. B. & Gloriam, D. E. Trends in GPCR drug discovery: new agents, targets and indications. Nat. Rev. Drug Discov. 16, 829–842 (2017).
Gonsiorek, W. et al. Pharmacological characterization of Sch527123, a potent allosteric CXCR1/CXCR2 antagonist. J. Pharmacol. Exp. Ther. 322, 477–485 (2007).
Legler, D. F. et al. Modulation of chemokine receptor function by cholesterol: new prospects for pharmacological intervention. Mol. Pharmacol. 91, 331–338 (2017).
Caffrey, M. & Cherezov, V. Crystallizing membrane proteins using lipidic mesophases. Nat. Protoc. 4, 706–731 (2009).
Cherezov, V. et al. Rastering strategy for screening and centring of microcrystal samples of human membrane proteins with a sub-10 μm size X-ray synchrotron beam. J. R. Soc. Interface 6, S587–S597 (2009).
Kabsch, W. Integration, scaling, space-group assignment and post-refinement. Acta Crystallogr. D 66, 133–144 (2010).
McCoy, A. J. et al. Phaser crystallographic software. J. Appl. Crystallogr. 40, 658–674 (2007).
Horcajada, C., Guinovart, J. J., Fita, I. & Ferrer, J. C. Crystal structure of an archaeal glycogen synthase: insights into oligomerization and substrate binding of eukaryotic glycogen synthases. J. Biol. Chem. 281, 2923–2931 (2006).
Adams, P. D. et al. PHENIX: a comprehensive Python-based system for macromolecular structure solution. Acta Crystallogr. D 66, 213–221 (2010).
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).
Emsley, P., Lohkamp, B., Scott, W. G. & Cowtan, K. Features and development of Coot. Acta Crystallogr. D 66, 486–501 (2010).
Mastronarde, D. N. Automated electron microscope tomography using robust prediction of specimen movements. J. Struct. Biol. 152, 36–51 (2005).
Punjani, A., Rubinstein, J. L., Fleet, D. J. & Brubaker, M. A. cryoSPARC: algorithms for rapid unsupervised cryo-EM structure determination. Nat. Methods 14, 290–296 (2017).
Heymann, J. B. Bsoft: image and molecular processing in electron microscopy. J. Struct. Biol. 133, 156–169 (2001).
Clore, G. M., Appella, E., Yamada, M., Matsushima, K. & Gronenborn, A. M. Three-dimensional structure of interleukin 8 in solution. Biochemistry 29, 1689–1696 (1990).
Pettersen, E. F. et al. UCSF Chimera—a visualization system for exploratory research and analysis. J. Comput. Chem. 25, 1605–1612 (2004).
Chen, V. B. et al. MolProbity: all-atom structure validation for macromolecular crystallography. Acta Crystallogr. D 66, 12–21 (2010).
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).
Huang, J. et al. CHARMM36m: an improved force field for folded and intrinsically disordered proteins. Nat. Methods 14, 71–73 (2017).
Vanommeslaeghe, K., Raman, E. P. & MacKerell, A. D., Jr. Automation of the CHARMM General Force Field (CGenFF) II: assignment of bonded parameters and partial atomic charges. J. Chem. Inf. Model. 52, 3155–3168 (2012).
Chan, H. C. S. et al. Exploring a new ligand binding site of G protein-coupled receptors. Chem. Sci. 9, 6480–6489 (2018).
Shaw, D. E. et al. Anton 2: raising the bar for performance and programmability in a special-purpose molecular dynamics supercomputer. In SC '14: Proc. International Conference for High Performance Computing, Networking, Storage and Analysis 41–53 (New Orleans, 2014).
Humphrey, W., Dalke, A. & Schulten, K. VMD: visual molecular dynamics. J. Mol. Graph. 14, 33–38 (1996).
Pronk, S. et al. GROMACS 4.5: a high-throughput and highly parallel open source molecular simulation toolkit. Bioinformatics 29, 845–854 (2013).
Barducci, A., Bussi, G. & Parrinello, M. Well-tempered metadynamics: a smoothly converging and tunable free-energy method. Phys. Rev. Lett. 100, 020603 (2008).
Barducci, A., Bonomi, M. & Parrinello, M. Metadynamics. Wiley Interdiscip. Rev. Comput. Mol. Sci. 1, 826–843 (2011).
Yuan, S., Filipek, S., Palczewski, K. & Vogel, H. Activation of G-protein-coupled receptors correlates with the formation of a continuous internal water pathway. Nat. Commun. 5, 4733 (2014).
Madhavi Sastry, G., Adzhigirey, M., Day, T., Annabhimoju, R. & Sherman, W. Protein and ligand preparation: parameters, protocols, and influence on virtual screening enrichments. J. Comput. Aided Mol. Des. 27, 221–234 (2013).
Barnea, G. et al. The genetic design of signaling cascades to record receptor activation. Proc. Natl Acad. Sci. USA 105, 64–69 (2008).
Kroeze, W. K. et al. PRESTO-Tango as an open-source resource for interrogation of the druggable human GPCRome. Nat. Struct. Mol. Biol. 22, 362–369 (2015).
Dolinsky, T. J., Nielsen, J. E., McCammon, J. A. & Baker, N. A. PDB2PQR: an automated pipeline for the setup of Poisson–Boltzmann electrostatics calculations. Nucleic Acids Res. 32, W665–W667 (2004).
Baker, N. A., Sept, D., Joseph, S., Holst, M. J. & McCammon, J. A. Electrostatics of nanosystems: application to microtubules and the ribosome. Proc. Natl Acad. Sci. USA 98, 10037–10041 (2001).
This work was supported by the National Natural Science Foundation of China grants 31930060 and 91953202 (Z.-J.L.), CAS Strategic Priority Research Program XDB37030104 (Z.-J.L.), the National Key Research and Development Program of China grant 2018YFA0507000 (T.H.), Shenzhen Institutes of Advanced Technology, CAS grant 1105150101 (S.Y. and S.L.) and the Interdisciplinary Centre for Mathematical and Computational Modelling in Warsaw grants GB70-3 and GB71-3 (S.Y.). We thank the Shanghai Municipal Government and ShanghaiTech University for financial support; J.-L. Liu and N. Chen at the cell expression core, Q.-W. Tan at the cloning core and staff members at the purification and assay cores of the iHuman Institute for their support; and G.-J. Song, I. Wilson and G. Yang for discussions. The cryo-EM data were collected at the Bio-Electron Microscopy Facility, ShanghaiTech University, with the assistance of D.-D. Liu and Y.-H. Liu. The synchrotron radiation experiments were performed at the BL41XU of SPring-8 with approval of the Japan Synchrotron Radiation Research Institute (JASRI) (proposals 2018B2722 and 2019A2522).
The authors declare no competing interests.
Peer review information Nature thanks Aashish Manglik 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
a, f, Superdex 200 size-exclusion chromatography elution profiles of the purified CXCR2–CXCL8 (dimer)–scFv16 complex (a) and CXCR2–CXCL8 (monomer)–scFv16 complex (f). b, g, SDS–PAGE analysis of the CXCL8 (dimer) complex (b) and CXCL8 (monomer) complex (g) after size exclusion. c, h, Representative cryo-EM image of the CXCR2–CXCL8 (dimer)–scFv16 complex (c) and CXCR2–CXCL8 (monomer)–scFv16 complex (h). Scale bars, 30 nm. d, i, Representative 2D classification showing distinct structural features of each component. Scale bars, 5 nm. e, j, Workflow of cryo-EM data processing for CXCR2–CXCL8 (dimer)–scFv16 complex (e) and CXCR2–CXCL8 (monomer)–scFv16 complex (j). Cryo-EM maps are coloured by local resolution (Å). Gold-standard FSC curves of the CXCR2–CXCL8 (dimer)–scFv16 and CXCR2–CXCL8 (monomer)–Gi–scFv16, indicating the resolution is 3.5 and 3.4 Å at the FSC = 0.143, respectively.
a, Cryo-EM density map and the model of CXCR2–CXCL8 (dimer)–Gi–scFv16 complex are shown for all transmembrane helices and helix 8 of CXCR2, and the cholesterol molecule. b, Cryo-EM density map and the model of the CXCR2–CXCL8 (monomer)–Gi–scFv16 complex are shown for all transmembrane helices and helix 8 of CXCR2, and the cholesterol molecule. c, d, Cryo-EM maps for the N-terminal residues (3-KELRCQCIK-11) of CXCL8 in the CXCR2–CXCL8 (dimer)–Gi–scFv16 complex (c) and CXCR2–CXCL8 (monomer)–Gi–scFv16 complex (d) structures.
Extended Data Fig. 3 Characterization of the CXCR2–00767013 complex and its comparison with antagonist-bound CCR2, CCR9 and CCR7.
a, Analytical size-exclusion chromatography profile. b, Crystal image. c, The overall structure of the CXCR2-00767013 complex with receptor in blue and PGS in light teal. The antagonist is shown as yellow sticks and sphere. The 2|Fo|–|Fc| map of 00767013 (in the box) is contoured at 1.0σ. d, Crystal packing of CXCR2-00767013. Colour schemes as in c. e, Addition of the allosteric antagonist 00767013 (blue) suppresses β-arrestin 2 recruitment in response to activation by CXCL8 monomer with half-maximum inhibitory concentration (IC50) of 0.62 ± 0.06 nM. The EC50 for monomeric CXCL8 is 0.38 ± 0.00 nM. Data are mean ± s.e.m. (n = 3). f–h, Overall structure comparison with CCR2 (PDB code 5T1A) (f), CCR9 (PDB code 5LWE) (g) and CCR7 (PDB code 6QZH) (h). The arrows indicate the relative orientation difference.
Extended Data Fig. 4 Structure comparison of the CXCR2–CXCL8 (dimer)–Gi–scFv16 and CXCR2–CXCL8 (monomer)–Gi–scFv16 complexes.
a, Overall structure comparison of dimeric and monomeric CXCL8-bound CXCR2–Gi–scFv16 complexes. b–g, Structure comparison of corresponding components in the two complex structures when superimposed using CXCR2 as reference. CXCL8 (b), CXCR2 (c), Gαi (d), Gβ (e), Gγ (f) and scFv16 (g).
a, Coarse-grained molecular dynamics simulation of the CXCL8 binding process. CXCL8 was placed 60 Å away from the N terminus of CXCR2. Step 1: after MD simulation, the N terminus of CXCR2 captured CXCL8 via electrostatic interactions. Small contact area was observed at this stage. Step 2: the N terminus of CXCR2 established an initial complex with CXCL8 and the contact area increased (486 ± 6 Å2). However, CXCL8 was still far away from the orthosteric site. Step 3: with the movement of the N terminus of CXCR2, CXCL8 was transferred to the entrance of CXCR2’s orthosteric site (1308 ± 6 Å2). b, The insertion process of CXCL8 sampled by all-atom metaMD simulation. Step 3 (from position a to b: CXCL8 was placed in an initial position that was identical to that step 2 sampled by coarse-grained simulation. After metaMD, CXCL8 was transferred to the vicinity of the CXCR2 orthosteric site. The energy barrier for this step is about 3.6 ± 0.3kcal mol−1. Step 4: by overcoming the energy barrier (6.6 ± 0.3 kcal mol−1) that was formed by ionic interactions between charged residues, the N-terminal tail finally inserts into the CXCR2. c, R.m.s.d. values of molecular dynamics simulations of the N terminus and overall structure of CXCR2–CXCL8 (dimer)–Gi complex during the 1-μs molecular dynamics simulations. See Supplementary Videos 1, 2.
Extended Data Fig. 6 The initial binding process of CXCL8 and CXCR2 in ten independent coarse-gained simulations.
a, The red chart represents the number of residue–residue contacts between CXCL8 with the first 25 residues of the CXCR2 N terminus; the blue chart shows the contacts between CXCL8 with residues beyond first 25 residues in CXCR2. Contact occurs if the residue-residue distance is shorter than 0.47 nm. CXCL8 binds to the 25 residues of the CXCR2 N terminus first in simulations (1–7), CXCL8 binds first to CXCR2 at the position other than N-terminal 25 residues in two simulations (9, 10), and one simulation (8) failed to result contacts. b, c, Representative N-terminal truncation variants’ effects on the agonism of wild-type CXCL8 (CXCL8-WT) and modified monomeric CXCL8 in the β-arrestin 2 recruitment assay. For CXCL8-WT: the EC50 values for CXCR2-WT, CXCR2-NΔ9, CXCR2-NΔ13 and CXCR2-NΔ19 are 0.19 ± 0.00 nM, 0.21 ± 0.00 nM, 0.31 ± 0.00 nM and 0.72 ± 0.04 nM, respectively. For CXCL8-monomer: the EC50 values for CXCR2-WT, CXCR2-NΔ9, CXCR2-NΔ13 and CXCR2-NΔ19 are 0.38 ± 0.00 nM, 0.50 ± 0.00 nM, 0.79 ± 0.12 nM and 1.48 ± 0.02 nM, respectively. Data are mean ± s.e.m. (n = 3).
Extended Data Fig. 7 Comparison of G proteins between CXCR2–CXCL8 (dimer)–Gi and GPCR–Gi, GPCR–Gs and GPCR–G11 complexes.
a, The structure of each GPCR–Gi/Gs/G11 complex is superposed onto CXCR2–CXCL8 (dimer)–Gi using receptor as reference. MOR (PDB code 6DDE), NTS1R (PDB code 6OS9), M1R (PDB code 6OIJ), β2AR (PDB code 3SN6). b, Comparison analysis of the interfaces formed between ICL2 of CXCR2 and Gαi, as well as between ICL2 of β2AR and Gαs. The sequence alignment of residues 34.50 and 34.51 among chemokine receptors is also presented. c, The sequence alignment of key residues which are within 4 Å interaction range in the solved GPCR–G protein complex structures. d, The sequence alignment of key residues involved in the solved chemokine receptors. Orange colour indicates the key residues discovered in the CXCR2–CXCL8–Gi complex.
Extended Data Fig. 8 Activation hallmarks of CXCR2 and the structure comparison of US28–CX3CL1 with the inactive and active CXCR2 structures.
a–c, Rearrangements of the PIF motif (a), toggle switch residues (b) and the NPxxY motif (c) between inactive (blue sticks) and active (orange sticks) states of CXCR2. d–f, Structure comparison of US28–CX3CL1 and inactive CXCR2. Side view (d), extracellular view (e) and intracellular view (f). g–i, Structure comparison of US28–CX3CL1 and active CXCR2. Side view (g), extracellular view (h) and intracellular view (i). j–l, Structure comparison of toggle switch residues (j), the PIF motif (k) and the NPxxY motif (l) between US28-CX3CL1 and active CXCR2.
a, Molecular model of the CXCR1–CXCL8 complex. CXCR1 is shown in white cartoon and CXCL8 is shown in red cartoon and shaded surface. b, Hydrophobic interactions between CXCR2 N terminus and CXCL8-A. Red, hydrophilic region; white, hydrophobic region. c, Electrostatic and surface properties of CXCL8 in the CXCL8–CXCR1 complex model. Electrostatic potentials (+8 kT per electron in blue and −8 kT per electron in red) mapped on the surfaces of the CXCL8 calculated at pH 7.0 using the programs PDB2PQR68 and APBS69. d, Diagram of the contacts between the CXCR2 N terminus and the N-loop of CXCL8. Acidic, basic, polar uncharged and hydrophobic residues are coloured red, blue, grey and green, respectively. sY, sulfotyrosine.
The sequence alignment of chemokine receptors using key residues which are within 4 Å interaction range in CXCR2-Gi complex structure as reference.
: The initial recognition process of CXCL8 and CXCR2 The process was sampled by coarse-grained (CG) long-time scale MD simulations. CXCL8 was placed 60 Å away from the N-terminus of CXCR2. After MD simulation, the N-terminus of CXCR2 captured CXCL8 via electrostatic interactions. N-terminus of CXCR2 established an initial complex with CXCL8. With the movement of the N-terminus of CXCR2, CXCL8 was transferred to the entrance of CXCR2’s orthosteric site.
: The N-terminal insertion process of CXCL8 into CXCR2. The process was sampled by all-atom metaMD simulations. CXCL8 was placed in an initial position that was sampled at the last step of CG simulation. After metaMD, CXCL8 was transferred to the vicinity of the CXCR2 orthosteric site. By overcoming the energy barrier that was formed by ionic interactions between charged residues, the N-terminal tail finally inserts into the CXCR2.
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Liu, K., Wu, L., Yuan, S. et al. Structural basis of CXC chemokine receptor 2 activation and signalling. Nature 585, 135–140 (2020). https://doi.org/10.1038/s41586-020-2492-5
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