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Characterization of determinants of ligand binding to the nicotinic acid receptor GPR109A (HM74A/PUMA-G).
Mol Pharmacol. 2005 Nov; 68(5):1271-80.MP

Abstract

The G-protein-coupled receptor GPR109A (HM74A/PUMA-G) has recently been shown to function as a receptor for nicotinic acid (niacin) and to mediate its antilipolytic effects. Nicotinic acid is able to strongly raise plasma levels of high-density lipoprotein cholesterol, a property that distinguishes nicotinic acid from other lipid-lowering drugs. To investigate the structural determinants of GPR109A ligand binding, we performed site-directed mutagenesis of putative ligand binding residues combined with generation of chimeric receptors consisting of GPR109A and its close relative GPR109B, which does not bind nicotinic acid. We could identify Asn86/Trp91 [transmembrane helix (TMH) 2/extracellular loop (ECL) 1], Arg111 (TMH3), Ser178 (ECL2), Phe276 (TMH7), and Tyr284 (TMH7) as amino acid residues critical for binding of nicotinic acid. Together with data from molecular modeling studies, our data suggest that the ligand binding pocket for nicotinic acid of GPR109A is distinct from that of most other group A receptors. Although Arg111 at TMH3 serves as the basic anchor point for the carboxylate ligands, the ring system of nicotinic acid is embedded between Trp91 at the junction TMH2/ECL1 and Phe276/Tyr284 at TMH7. The heterocyclic ring is also bound to Ser178 at ECL2 via an H-bond. These data will facilitate the design of new antidyslipidemic drugs acting via GPR109A.

Authors+Show Affiliations

Institute of Pharmacology, University of Heidelberg, Im Neuenheimer Feld 366, 69120 Heidelberg, Germany.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

16099840

Citation

Tunaru, Sorin, et al. "Characterization of Determinants of Ligand Binding to the Nicotinic Acid Receptor GPR109A (HM74A/PUMA-G)." Molecular Pharmacology, vol. 68, no. 5, 2005, pp. 1271-80.
Tunaru S, Lättig J, Kero J, et al. Characterization of determinants of ligand binding to the nicotinic acid receptor GPR109A (HM74A/PUMA-G). Mol Pharmacol. 2005;68(5):1271-80.
Tunaru, S., Lättig, J., Kero, J., Krause, G., & Offermanns, S. (2005). Characterization of determinants of ligand binding to the nicotinic acid receptor GPR109A (HM74A/PUMA-G). Molecular Pharmacology, 68(5), 1271-80.
Tunaru S, et al. Characterization of Determinants of Ligand Binding to the Nicotinic Acid Receptor GPR109A (HM74A/PUMA-G). Mol Pharmacol. 2005;68(5):1271-80. PubMed PMID: 16099840.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Characterization of determinants of ligand binding to the nicotinic acid receptor GPR109A (HM74A/PUMA-G). AU - Tunaru,Sorin, AU - Lättig,Jens, AU - Kero,Jukka, AU - Krause,Gerd, AU - Offermanns,Stefan, Y1 - 2005/08/11/ PY - 2005/8/16/pubmed PY - 2005/12/13/medline PY - 2005/8/16/entrez SP - 1271 EP - 80 JF - Molecular pharmacology JO - Mol Pharmacol VL - 68 IS - 5 N2 - The G-protein-coupled receptor GPR109A (HM74A/PUMA-G) has recently been shown to function as a receptor for nicotinic acid (niacin) and to mediate its antilipolytic effects. Nicotinic acid is able to strongly raise plasma levels of high-density lipoprotein cholesterol, a property that distinguishes nicotinic acid from other lipid-lowering drugs. To investigate the structural determinants of GPR109A ligand binding, we performed site-directed mutagenesis of putative ligand binding residues combined with generation of chimeric receptors consisting of GPR109A and its close relative GPR109B, which does not bind nicotinic acid. We could identify Asn86/Trp91 [transmembrane helix (TMH) 2/extracellular loop (ECL) 1], Arg111 (TMH3), Ser178 (ECL2), Phe276 (TMH7), and Tyr284 (TMH7) as amino acid residues critical for binding of nicotinic acid. Together with data from molecular modeling studies, our data suggest that the ligand binding pocket for nicotinic acid of GPR109A is distinct from that of most other group A receptors. Although Arg111 at TMH3 serves as the basic anchor point for the carboxylate ligands, the ring system of nicotinic acid is embedded between Trp91 at the junction TMH2/ECL1 and Phe276/Tyr284 at TMH7. The heterocyclic ring is also bound to Ser178 at ECL2 via an H-bond. These data will facilitate the design of new antidyslipidemic drugs acting via GPR109A. SN - 0026-895X UR - https://www.unboundmedicine.com/medline/citation/16099840/Characterization_of_determinants_of_ligand_binding_to_the_nicotinic_acid_receptor_GPR109A__HM74A/PUMA_G__ L2 - http://molpharm.aspetjournals.org/cgi/pmidlookup?view=long&pmid=16099840 DB - PRIME DP - Unbound Medicine ER -