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

Gerlach, L O; Jacobsen, J S; Jensen, Kasper LU ; Rosenkilde, M R; Skerlj, R T; Ryde, Ulf LU ; Bridger, G J and Schwartz, T W (2003) In Biochemistry 42(3). p.710-717
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... (More)
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. (Less)
Please use this url to cite or link to this publication:
author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Biochemistry
volume
42
issue
3
pages
710 - 717
publisher
The American Chemical Society
external identifiers
  • pmid:12534283
  • wos:000180568900013
  • scopus:0037469138
ISSN
0006-2960
DOI
10.1021/bi0264770
language
English
LU publication?
yes
id
ffe5b21d-ae62-470c-b596-9c673c721f90 (old id 128692)
date added to LUP
2007-07-17 09:56:13
date last changed
2018-01-28 03:27:43
@article{ffe5b21d-ae62-470c-b596-9c673c721f90,
  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.},
  author       = {Gerlach, L O and Jacobsen, J S and Jensen, Kasper and Rosenkilde, M R and Skerlj, R T and Ryde, Ulf and Bridger, G J and Schwartz, T W},
  issn         = {0006-2960},
  language     = {eng},
  number       = {3},
  pages        = {710--717},
  publisher    = {The American Chemical Society},
  series       = {Biochemistry},
  title        = {Metal ion enhanced binding of amd3100 to asp-262 in the cxcr4 receptor.},
  url          = {http://dx.doi.org/10.1021/bi0264770},
  volume       = {42},
  year         = {2003},
}