Role of 3D Structures in Understanding, Predicting, and Designing Molecular Interactions in the Chemokine Receptor Family

Kufareva, Irina; Abagyan, Ruben; Handel, Tracy M.

doi:10.1007/7355_2014_77

Cited by 5 publications

(9 citation statements)

References 216 publications

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“…Whereas previous dimeric structures of CXCR4 suggested that chemokines might bind receptors in a 2:1 CKR:chemokine stoichiometry (19, 20), the present structure demonstrates that the stoichiometry is 1:1, in agreement with a recent study (14). The chemokine interacts via its globular core with the receptor N-terminus (chemokine recognition site 1, CRS1 (21)) and via its N-terminus with the receptor TM pocket (CRS2) (Fig.…”

Section: Overall Complex Geometrysupporting

confidence: 92%

Crystal structure of the chemokine receptor CXCR4 in complex with a viral chemokine

Qin

Kufareva

Holden

et al. 2015

Science

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345

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Chemokines and their receptors control cell migration during development, immune system responses, and in numerous diseases including inflammation and cancer. The structural basis of receptor:chemokine recognition has been a long-standing unanswered question due to the challenges of structure determination for membrane protein complexes. Here we report the crystal structure of the chemokine receptor CXCR4 in complex with the viral chemokine antagonist vMIP-II at 3.1 Å resolution. The structure revealed a 1:1 stoichiometry and a more extensive binding interface than anticipated from the paradigmatic two-site model. The structure helped rationalize a large body of mutagenesis data, and together with modeling provided insights into CXCR4 interactions with its endogenous ligand CXCL12, its ability to recognize diverse ligands, and the specificity of CC and CXC receptors for their respective chemokines.

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Section: Overall Complex Geometrysupporting

confidence: 92%

Crystal structure of the chemokine receptor CXCR4 in complex with a viral chemokine

Qin

Kufareva

Holden

et al. 2015

Science

Self Cite

345

627

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“…77 The current section is dedicated to the compilation and analysis of the different strategies and results regarding binding mode prediction and its mutual contribution to drug design.…”

Section: Crystal Structure-based Analysis Cxcr4 Ccr2 Ccr5 Ccr9 Anmentioning

confidence: 99%

“…Chemokines are soluble proteins of low molecular mass (7–12 kDa) and about 70–90 residues , that share a conserved structural fold observed in the different chemokine crystal structures − (Figure a). The conformation of chemokines is stabilized by two disulfide bonds: a N-terminus coil of variable length, followed by the cysteine motif (C, CC, CXC, or CX 3 C), linked through an N-loop to the globular core of the chemokine, consisting on a 3 10 helix turn, three antiparallel beta strands, and followed by an α helix on the C-terminus.…”

Section: Crystal Structure-based Analysis Of the Effects Of Site-dire...mentioning

confidence: 99%

Structural Analysis of Chemokine Receptor–Ligand Interactions

et al. 2017

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This review focuses on the construction and application of structural chemokine receptor models for the elucidation of molecular determinants of chemokine receptor modulation and the structure-based discovery and design of chemokine receptor ligands. A comparative analysis of ligand binding pockets in chemokine receptors is presented, including a detailed description of the CXCR4, CCR2, CCR5, CCR9, and US28 X-ray structures, and their implication for modeling molecular interactions of chemokine receptors with small-molecule ligands, peptide ligands, and large antibodies and chemokines. These studies demonstrate how the integration of new structural information on chemokine receptors with extensive structure–activity relationship and site-directed mutagenesis data facilitates the prediction of the structure of chemokine receptor–ligand complexes that have not been crystallized. Finally, a review of structure-based ligand discovery and design studies based on chemokine receptor crystal structures and homology models illustrates the possibilities and challenges to find novel ligands for chemokine receptors.

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“…The cell-based and structure-based observations of CXCR4 dimers raised the key question as to whether CXCL12 binds to a single receptor subunit or to both subunits of the dimer, in a manner consistent with the two-site model. Several possible stoichiometries of the complex were suggested (7,35,36); among them, a 1:1 receptor:chemokine stoichiometry, a 2:1 stoichiometry with one chemokine molecule simultaneously binding to both subunits of a CXCR4 dimer, and a 2:2 stoichiometry with a chemokine dimer binding to the CXCR4 dimer. With respect to the latter, although CXCL12 dimers bind and act as partial agonists of CXCR4 (37), full agonist signaling requires a monomeric chemokine (37,38).…”

Section: Significancementioning

confidence: 99%

Stoichiometry and geometry of the CXC chemokine receptor 4 complex with CXC ligand 12: Molecular modeling and experimental validation

Kufareva

Stephens

Holden

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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124

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Chemokines and their receptors regulate cell migration during development, immune system function, and in inflammatory diseases, making them important therapeutic targets. Nevertheless, the structural basis of receptor:chemokine interaction is poorly understood. Adding to the complexity of the problem is the persistently dimeric behavior of receptors observed in cell-based studies, which in combination with structural and mutagenesis data, suggest several possibilities for receptor:chemokine complex stoichiometry. In this study, a combination of computational, functional, and biophysical approaches was used to elucidate the stoichiometry and geometry of the interaction between the CXC-type chemokine receptor 4 (CXCR4) and its ligand CXCL12. First, relevance and feasibility of a 2:1 stoichiometry hypothesis was probed using functional complementation experiments with multiple pairs of complementary nonfunctional CXCR4 mutants. Next, the importance of dimers of WT CXCR4 was explored using the strategy of dimer dilution, where WT receptor dimerization is disrupted by increasing expression of nonfunctional CXCR4 mutants. The results of these experiments were supportive of a 1:1 stoichiometry, although the latter could not simultaneously reconcile existing structural and mutagenesis data. To resolve the contradiction, cysteine trapping experiments were used to derive residue proximity constraints that enabled construction of a validated 1:1 receptor: chemokine model, consistent with the paradigmatic two-site hypothesis of receptor activation. The observation of a 1:1 stoichiometry is in line with accumulating evidence supporting monomers as minimal functional units of G protein-coupled receptors, and suggests transmission of conformational changes across the dimer interface as the most probable mechanism of altered signaling by receptor heterodimers.chemokine receptor | GPCR dimerization | molecular docking | functional complementation | cysteine trapping T he chemokine receptor CXCR4 regulates cell migration during many developmental processes (1, 2). Along with CCR5, it serves as one of the principal coreceptors for HIV entry into leukocytes (3), and is one of the most important chemokine receptors involved in cancer metastasis (4). Stromal-cell derived factor 1 (SDF-1 or CXCL12) was its only known ligand until recently, when CXCR4 was also shown to bind CXCL14 (5) and extracellular ubiquitin (6). Although structures of CXCR4 (7) and CCR5 (8) have been solved with synthetic antagonists, the structural basis for the interaction of CXCR4 (or any other chemokine receptor) with their natural ligands has yet to be determined. Numerous mutagenesis and NMR studies indicate that receptor:chemokine interactions involve two distinct sites (9-12), which has led to a two-site hypothesis of receptor activation (13). The so-called chemokine recognition site 1 (CRS1) (14) includes the N terminus of the receptor interacting with the globular core of the chemokine, whereas chemokine recognition site 2 (CRS2), located within the tra...

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Role of 3D Structures in Understanding, Predicting, and Designing Molecular Interactions in the Chemokine Receptor Family

Cited by 5 publications

References 216 publications

Crystal structure of the chemokine receptor CXCR4 in complex with a viral chemokine

Crystal structure of the chemokine receptor CXCR4 in complex with a viral chemokine

Structural Analysis of Chemokine Receptor–Ligand Interactions

Stoichiometry and geometry of the CXC chemokine receptor 4 complex with CXC ligand 12: Molecular modeling and experimental validation

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