Molecular mechanism of action of monocyclam versus bicyclam non-peptide antagonists in the CXCR4 chemokine receptor

Research output: Contribution to journal › Journal article › Research › peer-review

Standard

Molecular mechanism of action of monocyclam versus bicyclam non-peptide antagonists in the CXCR4 chemokine receptor. / Rosenkilde, Mette M; Gerlach, Lars-Ole; Hatse, Sigrid; Skerlj, Renato T; Schols, Dominique; Bridger, Gary J; Schwartz, Thue W.

In: Journal of Biological Chemistry, Vol. 282, No. 37, 2007, p. 27354-65.

Research output: Contribution to journal › Journal article › Research › peer-review

Harvard

Rosenkilde, MM, Gerlach, L-O, Hatse, S, Skerlj, RT, Schols, D, Bridger, GJ & Schwartz, TW 2007, 'Molecular mechanism of action of monocyclam versus bicyclam non-peptide antagonists in the CXCR4 chemokine receptor', Journal of Biological Chemistry, vol. 282, no. 37, pp. 27354-65. https://doi.org/10.1074/jbc.M704739200

APA

Rosenkilde, M. M., Gerlach, L-O., Hatse, S., Skerlj, R. T., Schols, D., Bridger, G. J., & Schwartz, T. W. (2007). Molecular mechanism of action of monocyclam versus bicyclam non-peptide antagonists in the CXCR4 chemokine receptor. Journal of Biological Chemistry, 282(37), 27354-65. https://doi.org/10.1074/jbc.M704739200

Vancouver

Rosenkilde MM, Gerlach L-O, Hatse S, Skerlj RT, Schols D, Bridger GJ et al. Molecular mechanism of action of monocyclam versus bicyclam non-peptide antagonists in the CXCR4 chemokine receptor. Journal of Biological Chemistry. 2007;282(37):27354-65. https://doi.org/10.1074/jbc.M704739200

Author

Rosenkilde, Mette M ; Gerlach, Lars-Ole ; Hatse, Sigrid ; Skerlj, Renato T ; Schols, Dominique ; Bridger, Gary J ; Schwartz, Thue W. / Molecular mechanism of action of monocyclam versus bicyclam non-peptide antagonists in the CXCR4 chemokine receptor. In: Journal of Biological Chemistry. 2007 ; Vol. 282, No. 37. pp. 27354-65.

Bibtex

@article{241030a0e61711ddbf70000ea68e967b,
title = "Molecular mechanism of action of monocyclam versus bicyclam non-peptide antagonists in the CXCR4 chemokine receptor",
abstract = "AMD3465 is a novel, nonpeptide CXCR4 antagonist and a potent inhibitor of HIV cell entry in that one of the four-nitrogen cyclam rings of the symmetrical, prototype bicyclam antagonist AMD3100 has been replaced by a two-nitrogen N-pyridinylmethylene moiety. This substitution induced an 8-fold higher affinity as determined against (125)I-12G5 monoclonal CXCR4 antibody binding, and a 22-fold higher potency in inhibition of CXCL12-induced signaling through phosphatidylinositol accumulation. Mutational mapping of AMD3465 and a series of analogs of this in a library of 23 mutants covering the main ligand binding pocket of the CXCR4 receptor demonstrated that the single cyclam ring of AMD3465 binds in the pocket around AspIV:20 (Asp(171)), in analogy with AMD3100, whereas the N-pyridinylmethylene moiety mimics the other cyclam ring through interactions with the two acidic anchor-point residues in transmembrane (TM)-VI (AspVI:23/Asp(262)) and TM-VII (GluVII:06/Glu(288)). Importantly, AMD3465 has picked up novel interaction sites, for example, His(281) located at the interface of extracellular loop 3 and TM-VII and HisIII:05 (His(113)) in the middle of the binding pocket. It is concluded that the simple N-pyridinylmethylene moiety of AMD3465 substitutes for one of the complex cyclam moieties of AMD3100 through an improved and in fact expanded interaction pattern mainly with residues located in the extracellular segments of TM-VI and -VII of the CXCR4 receptor. It is suggested that the remaining cyclam ring of AMD3465, which ensures the efficacious blocking of the receptor, in a similar manner can be replaced by chemical moieties allowing for, for example, oral bioavailability.",
author = "Rosenkilde, {Mette M} and Lars-Ole Gerlach and Sigrid Hatse and Skerlj, {Renato T} and Dominique Schols and Bridger, {Gary J} and Schwartz, {Thue W}",
note = "Keywords: Amino Acid Sequence; Animals; Anti-HIV Agents; Antibodies, Monoclonal; COS Cells; Cercopithecus aethiops; Heterocyclic Compounds; Humans; Molecular Sequence Data; Mutation; Pyridines; Receptors, CXCR4",
year = "2007",
doi = "10.1074/jbc.M704739200",
language = "English",
volume = "282",
pages = "27354--65",
journal = "Journal of Biological Chemistry",
issn = "0021-9258",
publisher = "American Society for Biochemistry and Molecular Biology, Inc.",
number = "37",

}

RIS

TY - JOUR

T1 - Molecular mechanism of action of monocyclam versus bicyclam non-peptide antagonists in the CXCR4 chemokine receptor

AU - Rosenkilde, Mette M

AU - Gerlach, Lars-Ole

AU - Hatse, Sigrid

AU - Skerlj, Renato T

AU - Schols, Dominique

AU - Bridger, Gary J

AU - Schwartz, Thue W

N1 - Keywords: Amino Acid Sequence; Animals; Anti-HIV Agents; Antibodies, Monoclonal; COS Cells; Cercopithecus aethiops; Heterocyclic Compounds; Humans; Molecular Sequence Data; Mutation; Pyridines; Receptors, CXCR4

PY - 2007

Y1 - 2007

N2 - AMD3465 is a novel, nonpeptide CXCR4 antagonist and a potent inhibitor of HIV cell entry in that one of the four-nitrogen cyclam rings of the symmetrical, prototype bicyclam antagonist AMD3100 has been replaced by a two-nitrogen N-pyridinylmethylene moiety. This substitution induced an 8-fold higher affinity as determined against (125)I-12G5 monoclonal CXCR4 antibody binding, and a 22-fold higher potency in inhibition of CXCL12-induced signaling through phosphatidylinositol accumulation. Mutational mapping of AMD3465 and a series of analogs of this in a library of 23 mutants covering the main ligand binding pocket of the CXCR4 receptor demonstrated that the single cyclam ring of AMD3465 binds in the pocket around AspIV:20 (Asp(171)), in analogy with AMD3100, whereas the N-pyridinylmethylene moiety mimics the other cyclam ring through interactions with the two acidic anchor-point residues in transmembrane (TM)-VI (AspVI:23/Asp(262)) and TM-VII (GluVII:06/Glu(288)). Importantly, AMD3465 has picked up novel interaction sites, for example, His(281) located at the interface of extracellular loop 3 and TM-VII and HisIII:05 (His(113)) in the middle of the binding pocket. It is concluded that the simple N-pyridinylmethylene moiety of AMD3465 substitutes for one of the complex cyclam moieties of AMD3100 through an improved and in fact expanded interaction pattern mainly with residues located in the extracellular segments of TM-VI and -VII of the CXCR4 receptor. It is suggested that the remaining cyclam ring of AMD3465, which ensures the efficacious blocking of the receptor, in a similar manner can be replaced by chemical moieties allowing for, for example, oral bioavailability.

AB - AMD3465 is a novel, nonpeptide CXCR4 antagonist and a potent inhibitor of HIV cell entry in that one of the four-nitrogen cyclam rings of the symmetrical, prototype bicyclam antagonist AMD3100 has been replaced by a two-nitrogen N-pyridinylmethylene moiety. This substitution induced an 8-fold higher affinity as determined against (125)I-12G5 monoclonal CXCR4 antibody binding, and a 22-fold higher potency in inhibition of CXCL12-induced signaling through phosphatidylinositol accumulation. Mutational mapping of AMD3465 and a series of analogs of this in a library of 23 mutants covering the main ligand binding pocket of the CXCR4 receptor demonstrated that the single cyclam ring of AMD3465 binds in the pocket around AspIV:20 (Asp(171)), in analogy with AMD3100, whereas the N-pyridinylmethylene moiety mimics the other cyclam ring through interactions with the two acidic anchor-point residues in transmembrane (TM)-VI (AspVI:23/Asp(262)) and TM-VII (GluVII:06/Glu(288)). Importantly, AMD3465 has picked up novel interaction sites, for example, His(281) located at the interface of extracellular loop 3 and TM-VII and HisIII:05 (His(113)) in the middle of the binding pocket. It is concluded that the simple N-pyridinylmethylene moiety of AMD3465 substitutes for one of the complex cyclam moieties of AMD3100 through an improved and in fact expanded interaction pattern mainly with residues located in the extracellular segments of TM-VI and -VII of the CXCR4 receptor. It is suggested that the remaining cyclam ring of AMD3465, which ensures the efficacious blocking of the receptor, in a similar manner can be replaced by chemical moieties allowing for, for example, oral bioavailability.

U2 - 10.1074/jbc.M704739200

DO - 10.1074/jbc.M704739200

M3 - Journal article

C2 - 17599916

VL - 282

SP - 27354

EP - 27365

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

IS - 37

ER -

ID: 9831031