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Molecular mechanism of AMD3100 antagonism in the CXCR4 receptor: transfer of binding site to the CXCR3 receptor.

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Standard

Molecular mechanism of AMD3100 antagonism in the CXCR4 receptor: transfer of binding site to the CXCR3 receptor. / Rosenkilde, Mette M; Gerlach, Lars-Ole; Jakobsen, Janus S; Skerlj, Renato T; Bridger, Gary J; Schwartz, Thue W.

I: Journal of Biological Chemistry, Bind 279, Nr. 4, 2003, s. 3033-41.

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningfagfællebedømt

Harvard

Rosenkilde, MM, Gerlach, L-O, Jakobsen, JS, Skerlj, RT, Bridger, GJ & Schwartz, TW 2003, 'Molecular mechanism of AMD3100 antagonism in the CXCR4 receptor: transfer of binding site to the CXCR3 receptor.', Journal of Biological Chemistry, bind 279, nr. 4, s. 3033-41. https://doi.org/10.1074/jbc.M309546200

APA

Rosenkilde, M. M., Gerlach, L-O., Jakobsen, J. S., Skerlj, R. T., Bridger, G. J., & Schwartz, T. W. (2003). Molecular mechanism of AMD3100 antagonism in the CXCR4 receptor: transfer of binding site to the CXCR3 receptor. Journal of Biological Chemistry, 279(4), 3033-41. https://doi.org/10.1074/jbc.M309546200

Vancouver

Rosenkilde MM, Gerlach L-O, Jakobsen JS, Skerlj RT, Bridger GJ, Schwartz TW. Molecular mechanism of AMD3100 antagonism in the CXCR4 receptor: transfer of binding site to the CXCR3 receptor. Journal of Biological Chemistry. 2003;279(4):3033-41. https://doi.org/10.1074/jbc.M309546200

Author

Rosenkilde, Mette M ; Gerlach, Lars-Ole ; Jakobsen, Janus S ; Skerlj, Renato T ; Bridger, Gary J ; Schwartz, Thue W. / Molecular mechanism of AMD3100 antagonism in the CXCR4 receptor: transfer of binding site to the CXCR3 receptor. I: Journal of Biological Chemistry. 2003 ; Bind 279, Nr. 4. s. 3033-41.

Bibtex

@article{b375ca6096ae11dd86a6000ea68e967b,
title = "Molecular mechanism of AMD3100 antagonism in the CXCR4 receptor: transfer of binding site to the CXCR3 receptor.",
abstract = "AMD3100 is a symmetric bicyclam, prototype non-peptide antagonist of the CXCR4 chemokine receptor. Mutational substitutions at 16 positions located in TM-III, -IV, -V, -VI, and -VII lining the main ligand-binding pocket of the CXCR4 receptor identified three acid residues: Asp(171) (AspIV:20), Asp(262) (AspVI:23), and Glu(288) (GluVII:06) as the main interaction points for AMD3100. Molecular modeling suggests that one cyclam ring of AMD3100 interacts with Asp(171) in TM-IV, whereas the other ring is sandwiched between the carboxylic acid groups of Asp(262) and Glu(288) from TM-VI and -VII, respectively. Metal ion binding in the cyclam rings of AMD3100 increased its dependence on Asp(262) and provided a tighter molecular map of the binding site, where borderline mutational hits became clear hits for the Zn(II)-loaded analog. The proposed binding site for AMD3100 was confirmed by a gradual build-up in the rather distinct CXCR3 receptor, for which the compound normally had no effect. Introduction of only a Glu at position VII:06 and the removal of a neutralizing Lys residue at position VII:02 resulted in a 1000-fold increase in affinity of AMD3100 to within 10-fold of its affinity in CXCR4. We conclude that AMD3100 binds through interactions with essentially only three acidic anchor-point residues, two of which are located at one end and the third at the opposite end of the main ligand-binding pocket of the CXCR4 receptor. We suggest that non-peptide antagonists with, for example, improved oral bioavailability can be designed to mimic this interaction and thereby efficiently and selectively block the CXCR4 receptor.",
author = "Rosenkilde, {Mette M} and Lars-Ole Gerlach and Jakobsen, {Janus S} and Skerlj, {Renato T} and Bridger, {Gary J} and Schwartz, {Thue W}",
note = "Keywords: Anti-HIV Agents; Binding Sites; Heterocyclic Compounds; Humans; Models, Molecular; Protein Binding; Protein Conformation; Receptors, CXCR4; Signal Transduction",
year = "2003",
doi = "10.1074/jbc.M309546200",
language = "English",
volume = "279",
pages = "3033--41",
journal = "Journal of Biological Chemistry",
issn = "0021-9258",
publisher = "American Society for Biochemistry and Molecular Biology, Inc.",
number = "4",

}

RIS

TY - JOUR

T1 - Molecular mechanism of AMD3100 antagonism in the CXCR4 receptor: transfer of binding site to the CXCR3 receptor.

AU - Rosenkilde, Mette M

AU - Gerlach, Lars-Ole

AU - Jakobsen, Janus S

AU - Skerlj, Renato T

AU - Bridger, Gary J

AU - Schwartz, Thue W

N1 - Keywords: Anti-HIV Agents; Binding Sites; Heterocyclic Compounds; Humans; Models, Molecular; Protein Binding; Protein Conformation; Receptors, CXCR4; Signal Transduction

PY - 2003

Y1 - 2003

N2 - AMD3100 is a symmetric bicyclam, prototype non-peptide antagonist of the CXCR4 chemokine receptor. Mutational substitutions at 16 positions located in TM-III, -IV, -V, -VI, and -VII lining the main ligand-binding pocket of the CXCR4 receptor identified three acid residues: Asp(171) (AspIV:20), Asp(262) (AspVI:23), and Glu(288) (GluVII:06) as the main interaction points for AMD3100. Molecular modeling suggests that one cyclam ring of AMD3100 interacts with Asp(171) in TM-IV, whereas the other ring is sandwiched between the carboxylic acid groups of Asp(262) and Glu(288) from TM-VI and -VII, respectively. Metal ion binding in the cyclam rings of AMD3100 increased its dependence on Asp(262) and provided a tighter molecular map of the binding site, where borderline mutational hits became clear hits for the Zn(II)-loaded analog. The proposed binding site for AMD3100 was confirmed by a gradual build-up in the rather distinct CXCR3 receptor, for which the compound normally had no effect. Introduction of only a Glu at position VII:06 and the removal of a neutralizing Lys residue at position VII:02 resulted in a 1000-fold increase in affinity of AMD3100 to within 10-fold of its affinity in CXCR4. We conclude that AMD3100 binds through interactions with essentially only three acidic anchor-point residues, two of which are located at one end and the third at the opposite end of the main ligand-binding pocket of the CXCR4 receptor. We suggest that non-peptide antagonists with, for example, improved oral bioavailability can be designed to mimic this interaction and thereby efficiently and selectively block the CXCR4 receptor.

AB - AMD3100 is a symmetric bicyclam, prototype non-peptide antagonist of the CXCR4 chemokine receptor. Mutational substitutions at 16 positions located in TM-III, -IV, -V, -VI, and -VII lining the main ligand-binding pocket of the CXCR4 receptor identified three acid residues: Asp(171) (AspIV:20), Asp(262) (AspVI:23), and Glu(288) (GluVII:06) as the main interaction points for AMD3100. Molecular modeling suggests that one cyclam ring of AMD3100 interacts with Asp(171) in TM-IV, whereas the other ring is sandwiched between the carboxylic acid groups of Asp(262) and Glu(288) from TM-VI and -VII, respectively. Metal ion binding in the cyclam rings of AMD3100 increased its dependence on Asp(262) and provided a tighter molecular map of the binding site, where borderline mutational hits became clear hits for the Zn(II)-loaded analog. The proposed binding site for AMD3100 was confirmed by a gradual build-up in the rather distinct CXCR3 receptor, for which the compound normally had no effect. Introduction of only a Glu at position VII:06 and the removal of a neutralizing Lys residue at position VII:02 resulted in a 1000-fold increase in affinity of AMD3100 to within 10-fold of its affinity in CXCR4. We conclude that AMD3100 binds through interactions with essentially only three acidic anchor-point residues, two of which are located at one end and the third at the opposite end of the main ligand-binding pocket of the CXCR4 receptor. We suggest that non-peptide antagonists with, for example, improved oral bioavailability can be designed to mimic this interaction and thereby efficiently and selectively block the CXCR4 receptor.

U2 - 10.1074/jbc.M309546200

DO - 10.1074/jbc.M309546200

M3 - Journal article

C2 - 14585837

VL - 279

SP - 3033

EP - 3041

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

IS - 4

ER -

ID: 6509858