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

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

SN - 0022-2623

VL - 55

SP - 8164

EP - 8177

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 18

ER -