Metal Ion Enhanced Binding of AMD3100 to Asp262 in the CXCR4 Receptor

Lars Ole Gerlach, Janus S. Jakobsen, Kasper Planeta Kepp, Mette R. Rosenkilde, Renato T. Skerlj, Ulf Ryde, Gary J. Bridger, Thue W. Schwartz

Research output: Contribution to journalJournal articleResearchpeer-review

Abstract

The affinity of AMD3100, a symmetrical nonpeptide antagonist composed of two 1,4,8,11-tetraazacyclotetradecane (cyclam) rings connected through a 1,4-dimethylene(phenylene) linker to the CXCR4 chemokine receptor was increased 7, 36, and 50-fold, respectively, by incorporation of the following: Cu2+, Zn2+, or Ni2+ into the cyclam rings of the compound. The rank order of the transition metal ions correlated with the calculated binding energy between free acetate and the metal ions coordinated in a cyclam ring. Construction of AMD3100 substituted with only a single Cu2+ or Ni2+ ion demonstrated that the increase in binding affinity of the metal ion substituted bicyclam is achieved through an enhanced interaction of just one of the ring systems. Mutational analysis of potential metal ion binding residues in the main ligand binding crevice of the CXCR4 receptor showed that although binding of the bicyclam is dependent on both Asp171 and Asp262, the enhancing effect of the metal ion was selectively eliminated by substitution of Asp262 located at the extracellular end of TM-VI. It is concluded that the increased binding affinity of the metal ion substituted AMD3100 is obtained through enhanced interaction of one of the cyclam ring systems with the carboxylate group ofAsp262. It is suggested that this occurs through a strong concomitant interaction of one of the oxygen's directly with the metal ion and the other oxygen to one of the nitrogens of the cyclam ring through a hydrogen bond.

Original languageEnglish
JournalBiochemistry
Volume42
Issue number3
Pages (from-to) 710-717
ISSN0006-2960
DOIs
Publication statusPublished - 2003
Externally publishedYes

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