Structures of the CXCR4 chemokine receptor in complex with small molecule and cyclic peptide antagonists

By Beili Wu, E. Chien, C. Mol, G. Fenalti, Wei Liu, Vsevolod Katritch, Ruben Abagyan, A. Brooun, P. Wells, F. Bi and 5 more. Science, 2010

1,770 citations recorded by the source corpus.

Regulating Migration The migration of cells around the body is an important factor in cancer development and the establishment of infection. Movement is induced by small proteins called chemokines, and so for a specific function, migration is controlled by a relevant chemokine binding to its respective receptor. This family of receptors is known as guanine (G) protein–coupled receptors, which span cell membranes to mediate between external signals from chemokines and internal mechanisms. The chemokine receptor CXCR4 is implicated in many types of cancer and in infection, and Wu et al. (p. 1066, published online 7 October; see the Report by Chien et al.) report on a series of crystal structures obtained for CXCR4 bound to small molecules. In every case, the same homodimer structure was observed, suggesting that the interface is functionally relevant. These structures offer insights into the interactions between CXCR4 and its natural chemokine, as well as with the virus HIV-1. Five crystal structures provide insight into chemokine and HIV-1 recognition. Chemokine receptors are critical regulators of cell migration in the context of immune surveillance, inflammation, and development. The G protein–coupled chemokine receptor CXCR4 is specifically implicated in cancer metastasis and HIV-1 infection. Here we report five independent crystal structures of CXCR4 bound to an antagonist small molecule IT1t and a cyclic peptide CVX15 at 2.5 to 3.2 angstrom resolution. All structures reveal a consistent homodimer with an interface including helices V and VI that may be involved in regulating signaling. The location and shape of the ligand-binding sites differ from other G protein–coupled receptors and are closer to the extracellular surface. These structures provide new clues about the interactions between CXCR4 and its natural ligand CXCL12, and with the HIV-1 glycoprotein gp120.

Subfields: Molecular Biology, Oncology, Radiology, Nuclear Medicine and Imaging

View Paper: https://www.semanticscholar.org/paper/b37197725e122c593283091fa038ac46456ec63c

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Citations in the corpus

GPCR-I-TASSER: A hybrid approach to G protein-coupled receptor structure modeling and the application to the human genome (2015, methodology): “Left to right columns are models for CXCR4 chemokine receptor withIT1t(PDB:3oe6)(Wuetal.,2010),CXCRreceptorwithCVX15(PDB:3oe0) (Wu et al., 2010), and dopamine D 3 with eticlopride (PDB: 3pbl) (Chien et al., 2010),respectively.”
The Protein Structure Initiative: achievements and visions for the future (2012, background): “Some important integral membrane protein structures, including several G protein-coupled receptors, known as GPCRs, and their complexes with ligands, have recently been determined in PSI-funded projects using both X-ray crystallography [62-71] andNMR spectroscopy [72,73].”
Computational approaches in target identification and drug discovery (2016, background): “There are several examples of the use of homology modeling in drug design, one of which the model of chemo-attractant receptor OXE-R based on the crystalstructureofCXCR4 [89]asatemplate.”
Modelling dynamics in protein crystal structures by ensemble refinement (2012, neutral): “…et al., 2000 ), 3QL3 ( Bhabha et al., 2011 ), 1YTT ( Burling et al., 1996 ), 3GWH ( Rodríguez et al., 2009 ), 1BV1 ( Gajhede et al., 1996 ), 1IEP ( Nagar et al., 2002 ), 2XFA ( Singh et al., 2011 ), 3ODU ( Wu et al., 2010 ), 1M52 ( Nagar et al., 2002 ), 3CM8 ( He et al., 2008 ) and 3RZE (…”
Generic GPCR Residue Numbers - Aligning Topology Maps Minding The Gaps (2014, background): “TRENDS in Pharmacological Sciences the co-crystallized 1T1t ligand prior to the CXCR4–1T1t crystal structure [56] in the GPCR Dock 2010 challenge [49,57] (Figure 4A).”
Ligand–receptor interaction platforms and their applications for drug discovery (2012, background): “These include rhodopsin [124], b2-adrenergic receptor [125], b1-adrenergic receptor [126], adenosine A2A receptor [127], CXCR4 chemokine receptor [128], dopamine D3 receptor [129], histamine H1 receptor [130], sphingosine 1-phosphate S1P1 receptor [131], muscarinic M3 acetylcholine receptor [132], m”
Assessment and Challenges of Ligand Docking into Comparative Models of G-Protein Coupled Receptors (2013, positive): “…includes the following G-protein coupled receptors: rhodopsin [14], b 1-adrenergic [15], b 2-adrenergic [16], A2A adenosine [17], CXCR4 chemokine [18], dopamine D3 [19], histamine H1 [20], S1P1 sphingosine 1-phosphate [21], M2 muscarinc acetylcholine [22], M3 muscarinic acetylecholine [23],…”
HMGB1 promotes recruitment of inflammatory cells to damaged tissues by forming a complex with CXCL12 and signaling via CXCR4 (2012, background): “The majority of the changes in CXCL12 involve residues 13–25, 40–45, and the C terminus, whereas the N terminus of CXCL12, in particular the flexible first 8 aa required for CXCR4 triggering (Crump et al., 1997; Wu et al., 2010), are clearly not affected by BoxB.”
HIV-1 antiretroviral drug therapy. (2012, methodology): “A rough model of maraviroc (MVC) binding to CCR5 in Figure 7 is based on data from a recently published structure of CXCR4 complexed to a small molecule, IT1t (Wu et al. 2010).”
HIV: cell binding and entry. (2012, background): “However, Wu et al. (2010) recently described five independent structures of CXCR4 bound to two different small-molecule antagonists, which have 4 Advanced Online Article.”
Structure-Function of the G-protein-Coupled Receptor Superfamily (2012, background): “Parallel dimers with substantial proteinprotein interface (>800 Å 2) have been found in crystal structures of 4 different GPCRs, including rhodopsin (83), CXCR4 (33), κ-opioid (36) and μ-opioid (34) receptors (see Table 3).”
Lifting the lid on GPCRs: the role of extracellular loops (2011, background): “ECL2 residues forming interactions with the named ligand are cited by their residue number for each receptor listed (Palczewski et al., 2000; Li et al., 2004; Cherezov et al., 2007; Jaakola et al., 2008; Warne et al., 2008; Chien et al., 2010; Wu et al., 2010).”