Mapping of the CXCR4 Antagonists Sample Clauses

Mapping of the CXCR4 Antagonists. Binding and SDF-1 N-terminus Binding Compared with previous GPCR structures, the binding cavity of CXCR4 is larger and more open with 3322 Å3 cavity volume. The small-molecule antagonist IT1t only occupies part of the pocket.[109] Several functional studies of mutant CXCR4 showed that Asp97, Asp187, Glu288, F87, D171 and F292 are required for SDF-1 binding, while the first three residue mutants impair SDF-1 signaling.[110, 111] The cyclic peptide TN14003 (T140) and CVX15 are CXCR4 antagonists of known structure. CXCR4 alanine scanning mutants identified that residues required for T140 binding are Xxx000, Xxx000, Xxx000, Gly207 and Asp262.[112] Recently, the crystallographic structure of CXCR4-CVX15 complex was released.[109] By combining the mutational analysis and the crystal structure, we can map the binding sites of the CXCR4 antagonists and the SDF-1 N-terminus. Mapping the T140 and CVX15 mutants onto the CXCR4 structure showed that these two peptide antagonists occupy similar sectors of the CXCR4 binding cavity, (Figures 7.3b-c) since most of the key residues for T140 binding are in close contact with CVX15. However, the SDF-1 N-terminus binds in another sector of the binding pocket, (Figure 7.3a) and a small overlap between peptide antagonist binding and SDF-1 N-terminus binding exists. (Figure 7.3d)
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Related to Mapping of the CXCR4 Antagonists

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