title: Structural basis for agonism and antagonism for a set of chemically related progesterone receptor modulators.
abstract: The progesterone receptor is able to bind to a large number and variety of ligands that elicit a broad range of transcriptional responses ranging from full agonism to full antagonism and numerous mixed profiles inbetween. We describe here two new progesterone receptor ligand binding domain x-ray structures bound to compounds from a structurally related but functionally divergent series, which show different binding modes corresponding to their agonistic or antagonistic nature. In addition, we present a third progesterone receptor ligand binding domain dimer bound to an agonist in monomer A and an antagonist in monomer B, which display binding modes in agreement with the earlier observation that agonists and antagonists from this series adopt different binding modes.
authors.affiliation: Department of Molecular Design and Informatics, DMPK, MSD, PO Box 20, 5340 BH Oss, The Netherlands. scott.lusher@merck.com
authors.forename: Scott J
authors.initials: SJ
authors.lastname: Lusher
authors.forename: Hans C A
authors.initials: HC
authors.lastname: Raaijmakers
authors.forename: Diep
authors.initials: D
authors.lastname: Vu-Pham
authors.forename: Koen
authors.initials: K
authors.lastname: Dechering
authors.forename: Tsang Wai
authors.initials: TW
authors.lastname: Lam
authors.forename: Angus R
authors.initials: AR
authors.lastname: Brown
authors.forename: Niall M
authors.initials: NM
authors.lastname: Hamilton
authors.forename: Olaf
authors.initials: O
authors.lastname: Nimz
authors.forename: Rolien
authors.initials: R
authors.lastname: Bosch
authors.forename: Ross
authors.initials: R
authors.lastname: McGuire
authors.forename: Arthur
authors.initials: A
authors.lastname: Oubrie
authors.forename: Jacob
authors.initials: J
authors.lastname: de Vlieg
mesh_terms: D000818:Animals; D001665:Binding Sites; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D018360:Crystallography, X-Ray / Q000379:methods; D019281:Dimerization; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D008024:Ligands; D015735:Mifepristone / Q000737:chemistry; D008958:Models, Molecular; D008968:Molecular Conformation; D009640:Norethindrone / Q000737:chemistry; D011374:Progesterone / Q000737:chemistry; D011485:Protein Binding; D011487:Protein Conformation; D011980:Receptors, Progesterone / Q000819:agonists* / Q000037:antagonists & inhibitors* / Q000378:metabolism*
chemical_list: D008024:Ligands; D011980:Receptors, Progesterone; D015735:Mifepristone; D011374:Progesterone; D009640:Norethindrone