Modulation in selectivity and allosteric properties of small-molecule ligands for CC-chemokine receptors

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Standard

Modulation in selectivity and allosteric properties of small-molecule ligands for CC-chemokine receptors. / Thiele, Stefanie; Malmgaard-Clausen, Mikkel; Engel-Andreasen, Jens; Steen, Anne; Rummel, Pia C; Nielsen, Mads C; Gloriam, David E.; Frimurer, Thomas Michael; Ulven, Trond; Rosenkilde, Mette.

I: Journal of Medicinal Chemistry, Bind 55, Nr. 18, 27.09.2012, s. 8164-77.

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt

Harvard

Thiele, S, Malmgaard-Clausen, M, Engel-Andreasen, J, Steen, A, Rummel, PC, Nielsen, MC, Gloriam, DE, Frimurer, TM, Ulven, T & Rosenkilde, M 2012, 'Modulation in selectivity and allosteric properties of small-molecule ligands for CC-chemokine receptors', Journal of Medicinal Chemistry, bind 55, nr. 18, s. 8164-77. https://doi.org/10.1021/jm301121j

APA

Thiele, S., Malmgaard-Clausen, M., Engel-Andreasen, J., Steen, A., Rummel, P. C., Nielsen, M. C., Gloriam, D. E., Frimurer, T. M., Ulven, T., & Rosenkilde, M. (2012). Modulation in selectivity and allosteric properties of small-molecule ligands for CC-chemokine receptors. Journal of Medicinal Chemistry, 55(18), 8164-77. https://doi.org/10.1021/jm301121j

Vancouver

Thiele S, Malmgaard-Clausen M, Engel-Andreasen J, Steen A, Rummel PC, Nielsen MC o.a. Modulation in selectivity and allosteric properties of small-molecule ligands for CC-chemokine receptors. Journal of Medicinal Chemistry. 2012 sep. 27;55(18):8164-77. https://doi.org/10.1021/jm301121j

Author

Thiele, Stefanie ; Malmgaard-Clausen, Mikkel ; Engel-Andreasen, Jens ; Steen, Anne ; Rummel, Pia C ; Nielsen, Mads C ; Gloriam, David E. ; Frimurer, Thomas Michael ; Ulven, Trond ; Rosenkilde, Mette. / Modulation in selectivity and allosteric properties of small-molecule ligands for CC-chemokine receptors. I: Journal of Medicinal Chemistry. 2012 ; Bind 55, Nr. 18. s. 8164-77.

Bibtex

@article{4b3a450a041545898e0d9b585c1cd2f4,
title = "Modulation in selectivity and allosteric properties of small-molecule ligands for CC-chemokine receptors",
abstract = "Among 18 human chemokine receptors, CCR1, CCR4, CCR5, and CCR8 were activated by metal ion Zn(II) or Cu(II) in complex with 2,2'-bipyridine or 1,10-phenanthroline with similar potencies (EC(50) from 3.9 to 172 μM). Besides being agonists, they acted as selective allosteric enhancers of CCL3. These actions were dependent on a conserved glutamic acid at TM-7 (VII:06/7.39). A screening of 20 chelator analogues in complex with Zn(II) identified compounds with increased potencies, with 7 reaching highest potency at CCR1 (EC(50) of 0.85 μM), 20 at CCR8 (0.39 μM), and 8 at CCR5 (1.0 μM). Altered selectivity for CCR1 and CCR8 over CCR5 (11, 12) and a receptor-dependent separation of allosteric from intrinsic properties were achieved (20). The pocket similarities of CCR1 and CCR8, contrary to CCR5 as proposed by the ligand screen, were elaborated by computational modeling. These studies facilitate exploration of chemokine receptors as possible targets for therapeutic intervention.",
keywords = "Allosteric Regulation, Animals, Binding Sites, COS Cells, Cercopithecus aethiops, Chelating Agents, Copper, Glutamic Acid, Humans, Ligands, Models, Molecular, Organometallic Compounds, Protein Structure, Tertiary, Pyridines, Receptors, CCR, Substrate Specificity, Zinc",
author = "Stefanie Thiele and Mikkel Malmgaard-Clausen and Jens Engel-Andreasen and Anne Steen and Rummel, {Pia C} and Nielsen, {Mads C} and Gloriam, {David E.} and Frimurer, {Thomas Michael} and Trond Ulven and Mette Rosenkilde",
year = "2012",
month = sep,
day = "27",
doi = "10.1021/jm301121j",
language = "English",
volume = "55",
pages = "8164--77",
journal = "Journal of Medicinal Chemistry",
issn = "0022-2623",
publisher = "American Chemical Society",
number = "18",

}

RIS

TY - JOUR

T1 - Modulation in selectivity and allosteric properties of small-molecule ligands for CC-chemokine receptors

AU - Thiele, Stefanie

AU - Malmgaard-Clausen, Mikkel

AU - Engel-Andreasen, Jens

AU - Steen, Anne

AU - Rummel, Pia C

AU - Nielsen, Mads C

AU - Gloriam, David E.

AU - Frimurer, Thomas Michael

AU - Ulven, Trond

AU - Rosenkilde, Mette

PY - 2012/9/27

Y1 - 2012/9/27

N2 - Among 18 human chemokine receptors, CCR1, CCR4, CCR5, and CCR8 were activated by metal ion Zn(II) or Cu(II) in complex with 2,2'-bipyridine or 1,10-phenanthroline with similar potencies (EC(50) from 3.9 to 172 μM). Besides being agonists, they acted as selective allosteric enhancers of CCL3. These actions were dependent on a conserved glutamic acid at TM-7 (VII:06/7.39). A screening of 20 chelator analogues in complex with Zn(II) identified compounds with increased potencies, with 7 reaching highest potency at CCR1 (EC(50) of 0.85 μM), 20 at CCR8 (0.39 μM), and 8 at CCR5 (1.0 μM). Altered selectivity for CCR1 and CCR8 over CCR5 (11, 12) and a receptor-dependent separation of allosteric from intrinsic properties were achieved (20). The pocket similarities of CCR1 and CCR8, contrary to CCR5 as proposed by the ligand screen, were elaborated by computational modeling. These studies facilitate exploration of chemokine receptors as possible targets for therapeutic intervention.

AB - Among 18 human chemokine receptors, CCR1, CCR4, CCR5, and CCR8 were activated by metal ion Zn(II) or Cu(II) in complex with 2,2'-bipyridine or 1,10-phenanthroline with similar potencies (EC(50) from 3.9 to 172 μM). Besides being agonists, they acted as selective allosteric enhancers of CCL3. These actions were dependent on a conserved glutamic acid at TM-7 (VII:06/7.39). A screening of 20 chelator analogues in complex with Zn(II) identified compounds with increased potencies, with 7 reaching highest potency at CCR1 (EC(50) of 0.85 μM), 20 at CCR8 (0.39 μM), and 8 at CCR5 (1.0 μM). Altered selectivity for CCR1 and CCR8 over CCR5 (11, 12) and a receptor-dependent separation of allosteric from intrinsic properties were achieved (20). The pocket similarities of CCR1 and CCR8, contrary to CCR5 as proposed by the ligand screen, were elaborated by computational modeling. These studies facilitate exploration of chemokine receptors as possible targets for therapeutic intervention.

KW - Allosteric Regulation

KW - Animals

KW - Binding Sites

KW - COS Cells

KW - Cercopithecus aethiops

KW - Chelating Agents

KW - Copper

KW - Glutamic Acid

KW - Humans

KW - Ligands

KW - Models, Molecular

KW - Organometallic Compounds

KW - Protein Structure, Tertiary

KW - Pyridines

KW - Receptors, CCR

KW - Substrate Specificity

KW - Zinc

U2 - 10.1021/jm301121j

DO - 10.1021/jm301121j

M3 - Journal article

C2 - 22957890

VL - 55

SP - 8164

EP - 8177

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

IS - 18

ER -

ID: 45811325