title: Determination of different putative allosteric binding pockets at the lutropin receptor by using diverse drug-like low molecular weight ligands.
abstract: The lutropin/choriogonadotrophin receptor (LHCGR) is a family A G protein-coupled receptor (GPCR) which binds the endogenous hormone-ligands at the large extracellular domain. In contrast, several drug-like low-molecular-weight ligands (LMWs) have been reported to interact allosterically within the seven transmembrane domain (7TMD) of the LHCGR. Here, we were interested to study the putative allosteric LHCGR binding region with focus on the determination of two pockets for LMW ligands. A library of compounds was screened for their ability to modify the binding of an allosteric radiolabeled LMW agonist [³H]Org 43553. Further experimental and computational studies revealed that the putative binding pocket for a newly identified allosteric enhancer (LUF5419) and a previously described allosteric inhibitor (LUF5771) are overlapping and that this site is different from the Org 43553 binding site. The present study showed that these compounds are useful tools to reveal details on different allosteric binding sites located within the 7TMD of the LHCGR.
authors.affiliation: Division of Medicinal Chemistry, Leiden/Amsterdam Center for Drug Research, University of Leiden, P.O. Box 9502, 2300 RA Leiden, The Netherlands. l.h.heitman@lacdr.leidenuniv.nl
authors.forename: Laura H
authors.initials: LH
authors.lastname: Heitman
authors.forename: Gunnar
authors.initials: G
authors.lastname: Kleinau
authors.forename: Johannes
authors.initials: J
authors.lastname: Brussee
authors.forename: Gerd
authors.initials: G
authors.lastname: Krause
authors.forename: Adriaan P
authors.initials: AP
authors.lastname: Ijzerman
mesh_terms: D000495:Allosteric Site; D000818:Animals; D001549:Benzamides / Q000378:metabolism / Q000494:pharmacology; D001665:Binding Sites; D016466:CHO Cells; D002219:Carbamates / Q000378:metabolism / Q000494:pharmacology; D006224:Cricetinae; D008024:Ligands; D008958:Models, Molecular; D011485:Protein Binding; D017433:Protein Structure, Secondary; D011743:Pyrimidines / Q000378:metabolism; D011974:Receptors, LH / Q000378:metabolism*; D013730:Terphenyl Compounds / Q000378:metabolism / Q000494:pharmacology; D013844:Thiazoles / Q000378:metabolism / Q000494:pharmacology; D013876:Thiophenes / Q000378:metabolism
chemical_list: C526583:5-amino-2-methylsulfanyl-4-(3-(2-morpholin-4-ylacetylamino)phenyl)thieno(2,3-d)pyrimidine-6-carboxylic acid tert-butylamide; D001549:Benzamides; D002219:Carbamates; D008024:Ligands; D011743:Pyrimidines; D011974:Receptors, LH; D013730:Terphenyl Compounds; D013844:Thiazoles; D013876:Thiophenes; C540186:cyclopentylcarbamic acid (1,1',2',1'')terphenyl-5'-yl ester