Progesterone receptor ligand binding pocket flexibility: crystal structures of the norethindrone and mometasone furoate complexes.

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Madauss KP, Deng SJ, Austin RJ, Lambert MH, McLay I, Pritchard J, Short SA, Stewart EL, Uings IJ, Williams SP

Progesterone receptor ligand binding pocket flexibility: crystal structures of the norethindrone and mometasone furoate complexes.

J Med Chem. 2004 Jun 17;47(13):3381-7.

PubMed ID

15189034 [ View in PubMed

]

Abstract

Although progesterone, the natural ligand of the progesterone receptor (PR), has a hydrogen atom at the 17alpha position, other potent steroid agonists such as norethindrone and mometasone furoate have larger substituents at this position that are accommodated by the PR ligand binding pocket. Crystallographic analysis of PR ligand binding domain complexes clearly demonstrated that these moieties were accommodated by local shifts of the protein main chain and by adoption of alternative side chain rotamer conformations of ligand-proximal amino acids. These conformational changes imparted a ligand-specific volume to the binding pocket, from 490 A3 in the metribolone complex to 520 A3 in the norethindrone complex, 565 A3 in the progesterone complex, and 730 A3 in the mometasone furoate complex. Despite these marked alterations in binding pocket volume, critical interactions essential for establishment of an active AF2 conformation were maintained.

DrugBank Data that Cites this Article

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Mometasone	Progesterone receptor	Protein	Humans	Unknown	Agonist	Details
Mometasone furoate	Progesterone receptor	Protein	Humans	Unknown	Not Available	Details

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Norethisterone	Progesterone receptor	Kd (nM)	0.4	N/A	N/A	Details