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Activation of the CXCR3 Chemokine Receptor through Anchoring of a Small Molecule Chelator Ligand between TM-III, -IV, and -VI

Laboratory for Molecular Pharmacology, Department of Pharmacology, University of Copenhagen, Copenhagen, Denmark (M.M.R., M.B.A., R.N., T.W.S.); and 7TM Pharma A/S, Hørsholm, Denmark (R.N., T.M.F., T.W.S.)

Seven transmembrane segment (7TM) receptors are activated through a common, still rather unclear molecular mechanism by a variety of chemical messengers ranging from monoamines to large proteins. By introducing a His residue at position III:05 in the CXCR3 receptor a metal ion site was built between the extracellular ends of transmembrane (TM) III and TM-IV to anchor aromatic chelators at a location corresponding to the presumed binding pocket for adrenergic receptor agonists. In this construct, free metal ions had no agonistic effect in accordance with the optimal geometry of the metal ion site in molecular models built over the inactive form of rhodopsin. In contrast, the aromatic chelators bipyridine or phenanthrolene in complex with Zn(II) or Cu(II) acted as potent agonists displaying signaling efficacies similar to or even better than the endogenous chemokine agonists. Molecular modeling and molecular simulations combined with mutational analysis indicated that the metal ion site-anchored chelators act as agonists by establishing an aromatic-aromatic, second-site interaction with TyrVI:16 on the inner face of TM-VI. It is noteworthy that this interaction required that the extracellular segment of TM-VI moves inward in the direction of TM-III, whereby TyrVI:16 together with the chelators complete an "aromatic zipper" also comprising PheIII:08 (corresponding to the monoamine receptor anchoring point) and TyrVII:10 (corresponding to the retinal attachment site in rhodopsin). Chemokine agonism was independent of this aromatic zipper. It is proposed that in rhodopsin-like 7TM receptors, small-molecule compounds in general act as agonists in a similar manner as here demonstrated with the artificial, metal ion site anchored chelators, by holding TM-VI bent inward.

Address correspondence to: Thue W. Schwartz, Laboratory for Molecular Pharmacology, Department of Pharmacology, The Panum Institute, University of Copenhagen, Blegdamsvej 3b, DK-2200, Copenhagen, Denmark. E-mail: schwartz{at}molpharm.dk

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