Progesterone Receptor Ligand Binding Pocket Flexibility:  Crystal Structures of the Norethindrone and Mometasone Furoate Complexes

Madauss, Kevin P.; Deng, Su-Jun; Austin, Robert J.; Lambert, Millard H.; McLay, Iain M.; Pritchard, John B.; Short, Steven A.; Stewart, Eugene L.; Uings, Ian J.; Williams, Shawn P.

doi:10.1021/jm030640n

Cited by 79 publications

(57 citation statements)

References 23 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Ligandinduced adjustment in the PR binding pocket has also been observed in the recently solved x-ray structures of norethindrone and mometasone furoate (47), where local shifts in both protein main chain and side chain conformations allow these ligands to be accommodated.…”

Section: Figmentioning

confidence: 70%

Molecular and Pharmacological Properties of a Potent and Selective Novel Nonsteroidal Progesterone Receptor Agonist Tanaproget

Zhang

Olland

Zhu

et al. 2005

Journal of Biological Chemistry

View full text Add to dashboard Cite

Progesterone receptor (PR) agonists have several important applications in women's health, such as in oral contraception and post-menopausal hormone therapy. Currently, all PR agonists used clinically are steroids. Because of their interactions with other steroid receptors, steroid-metabolizing enzymes, or other steroid-signaling pathways, these drugs can pose significant side effects in some women. Efforts to discover novel nonsteroidal PR agonists with improved biological properties led to the discovery of tanaproget (TNPR). TNPR binds to the PR from various species with a higher relative affinity than reference steroidal progestins. In T47D cells, TNPR induces alkaline phosphatase activity with an EC 50 value of 0.1 nM, comparable with potent steroidal progestins such as medroxyprogesterone acetate (MPA) and trimegestone (TMG), albeit with a reduced efficacy (ϳ60%). In a mammalian two-hybrid assay to measure PR agonist-induced interaction between steroid receptor co-activator-1 and PR, TNPR showed similar potency (EC 50 value of 0.02 nM) and efficacy to MPA and TMG. Importantly, in key animal models such as the rat ovulation inhibition assay, TNPR demonstrates full efficacy and an enhanced progestational potency (30-fold) when compared with MPA and TMG. Furthermore, TNPR has relatively weak interactions with other steroid receptors and binding proteins and little effect on cytochrome P450 metabolic pathways. Finally, the three-dimensional crystal structure of the PR ligand binding domain with TNPR has been delineated to demonstrate how this nonsteroidal ligand achieves its high binding affinity. Therefore, TNPR is a structurally novel and very selective PR agonist with an improved preclinical pharmacological profile.

show abstract

Section: Figmentioning

confidence: 70%

Molecular and Pharmacological Properties of a Potent and Selective Novel Nonsteroidal Progesterone Receptor Agonist Tanaproget

Zhang

Olland

Zhu

et al. 2005

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…The maps account for the entire ligand and enable precise positioning of the ligand with high confidence. Published x-ray structures of PR bound to norethindrone (32) and RU486 (21) show direct interactions between the 3-keto groups from each ligand to Gln 725 and Arg 766 as well as a structurally conserved water molecule completing complex H-bonding networks as shown in Fig. 4, A and B. OrgA, as shown in Fig.…”

Section: Resultsmentioning

confidence: 97%

Structural Basis for Agonism and Antagonism for a Set of Chemically Related Progesterone Receptor Modulators

Lusher¹,

Raaijmakers²,

Vu-Pham³

et al. 2011

Journal of Biological Chemistry

View full text Add to dashboard Cite

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.

show abstract

“…In all of these cases, coexpression with a high-affinity ligand was key to obtaining protein for structural studies Matias et al, 2000;Sack et al, 2001;He et al, 2004;Madauss et al, 2004;Fig. 1 Hassell et al…”

Section: Co-expression With Ligands Of Interestmentioning

confidence: 99%

Crystallization of protein–ligand complexes

Hassell

An²,

Bledsoe

et al. 2006

Acta Crystallogr D Biol Crystallogr

Self Cite

131

View full text Add to dashboard Cite

Obtaining diffraction-quality crystals has long been a bottleneck in solving the three-dimensional structures of proteins. Often proteins may be stabilized when they are complexed with a substrate, nucleic acid, cofactor or small molecule. These ligands, on the other hand, have the potential to induce significant conformational changes to the protein and ab initio screening may be required to find a new crystal form. This paper presents an overview of strategies in the following areas for obtaining crystals of protein-ligand complexes: (i) coexpression of the protein with the ligands of interest, (ii) use of the ligands during protein purification, (iii) cocrystallization and (iv) soaks.

show abstract

Progesterone Receptor Ligand Binding Pocket Flexibility: Crystal Structures of the Norethindrone and Mometasone Furoate Complexes

Cited by 79 publications

References 23 publications

Molecular and Pharmacological Properties of a Potent and Selective Novel Nonsteroidal Progesterone Receptor Agonist Tanaproget

Molecular and Pharmacological Properties of a Potent and Selective Novel Nonsteroidal Progesterone Receptor Agonist Tanaproget

Structural Basis for Agonism and Antagonism for a Set of Chemically Related Progesterone Receptor Modulators

Crystallization of protein–ligand complexes

Contact Info

Product

Resources

About