Metal ion enhanced binding of amd3100 to asp-262 in the cxcr4 receptor.

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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 of Asp262. 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.

Detaljer

Författare
  • L O Gerlach
  • J S Jacobsen
  • Kasper Jensen
  • M R Rosenkilde
  • R T Skerlj
  • Ulf Ryde
  • G J Bridger
  • T W Schwartz
Enheter & grupper
Forskningsområden

Ämnesklassifikation (UKÄ) – OBLIGATORISK

  • Biokemi och molekylärbiologi
Originalspråkengelska
Sidor (från-till)710-717
TidskriftBiochemistry
Volym42
Utgivningsnummer3
StatusPublished - 2003
PublikationskategoriForskning
Peer review utfördJa