Probing the Molecular Interactions between CXC Chemokine Receptor 4 (CXCR4) and an Arginine-Based Tripeptidomimetic Antagonist (KRH-1636)

Abstract

Abstract:We here report an experimentally verified binding mode for the known tripeptidomimetic CXCR4 antagonist KRH-1636 (1). A limited SAR study was first conducted based on the three functionalities of 1, followed by site-directed mutagenesis studies. The receptor mapping showed that both the potency and affinity of 1 were dependent on the transmembrane residues His 113 , Asp 171 , Asp 262 , and His 281 , and also suggested the involvement of

Structural Analysis of Chemokine Receptor–Ligand Interactions

“…A large amount of site-directed mutagenesis studies, covering almost all chemokine receptors (CCR1, 50,51 CCR2, 15,52,53,93,94 CCR3, 95 CCR5, 54−58,90,96−100 CCR8, 59 CCR9, 16 CXCR1, 101−103 CXCR2, 60,61 CXCR3, 63−67,104 CXCR4, 13,21,68−72,74,105−114 CXCR7, 115 and US28 75 ) have resulted in 2709 mutation data points, covering 343 different mutants (Figures 10–13, 18–20). About half of the mutation data (1389 data points, covering 238 different mutants) have resulted from studies with 63 unique small-molecule ligands (molecular weight ≤650), of which 46 are shown in Figures 11–13, 18–20.…”

“…About half of the mutation data (1389 data points, covering 238 different mutants) have resulted from studies with 63 unique small-molecule ligands (molecular weight ≤650), of which 46 are shown in Figures 11–13, 18–20. 16,21,50−61,63,64,67−72,93,100,116 A total number of 236 mutants have been investigated to study a total of 24 different chemokine ligands resulting in 645 data points, 13,21,52−55,58−61,63−69,72,74,75,90,94,97−99,105,106,108−113,115 while 606 mutation data points have been used to study the epitopes of nine different antibodies. 21,68,71,72,96,106,107 Sections 3.1 and 3.2 will provide crystal structure-based analyses of CXCR4, CCR2, CCR5, CCR9, and US28 mutation data, while section 5 will discuss how receptor mutation data can be used to model interactions between small-molecule ligands and chemokine receptors for which no crystal structure has been reported.…”

“…Mutation studies indicate that D 2.63 is important for the binding of ligands 15 (KRH-1636) 21 and 13 (69) to CXCR4 (Figure 11) 21,69 and also play a role in small-molecule ligand binding to CXCR3 (section 5.5). 63 It should be noted however that D 2.63 is not conserved within the chemokine receptor subfamily.…”

“…The residue at position 45.51 is however not conserved among chemokine receptors (Figure 2) and mutation of this residue seems to be receptor and ligand dependent. 21,54,56,57,68 …”

“…17−19 The first crystal structures of the 7TM domains of chemokine receptors (CXCR4, CCR2, CCR5, CCR9, and US28) have been solved only in the past six years. 11−16 These small-molecule, 12,15,16 peptide, 11 and chemokine 13,14 bound structures have provided a structural basis to validate and improve chemokine receptor homology modeling studies, 20 to rationalize SAR data 21,22 and to perform structure-based virtual screening and ligand design studies. 23−30 Chemokine homology models and de novo receptor models have already been successfully used to identify new ligands for CCR3, 31 CCR4, 32,33 CCR5, 34,35 CXCR3, 26 CXCR4, 24,26−30,36,37 and CXCR7, 38 and the recently released crystal structures have increased the possibilities to study and predict structural chemokine receptor–ligand interactions.…”