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

Stefanie Thiele; Mikkel Malmgaard-Clausen; Jens Engel-Andreasen; Anne Steen; Pia C Rummel; Mads C Nielsen; David E. Gloriam; Thomas Michael Frimurer; Trond Ulven; Mette Rosenkilde

doi:10.1021/jm301121j

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

Stefanie Thiele, Mikkel Malmgaard-Clausen, Jens Engel-Andreasen, Anne Steen, Pia C Rummel, Mads C Nielsen, David E. Gloriam, Thomas Michael Frimurer, Trond Ulven, Mette Rosenkilde

23 Citations (Scopus)

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.

Original language	English
Journal	Journal of Medicinal Chemistry
Volume	55
Issue number	18
Pages (from-to)	8164-77
Number of pages	14
ISSN	0022-2623
DOIs	https://doi.org/10.1021/jm301121j
Publication status	Published - 27 Sept 2012

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

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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",

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journal = "Journal of Medicinal Chemistry",

issn = "0022-2623",

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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

SN - 0022-2623

VL - 55

SP - 8164

EP - 8177

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 18

ER -

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

Abstract

Keywords

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