4a2j › Citations

X-ray structures of progesterone receptor ligand binding domain in its agonist state reveal differing mechanisms for mixed profiles of 11β-substituted steroids.

Lusher SJ, Raaijmakers HC, Vu-Pham D, Kazemier B, Bosch R, McGuire R, Azevedo R, Hamersma H, Dechering K, Oubrie A, van Duin M, de Vlieg J
J Biol Chem 287 20333-43 (2012)
Cited: 19 times
EuropePMC logo PMID: 22535964

Abstract

We present here the x-ray structures of the progesterone receptor (PR) in complex with two mixed profile PR modulators whose functional activity results from two differing molecular mechanisms. The structure of Asoprisnil bound to the agonist state of PR demonstrates the contribution of the ligand to increasing stability of the agonist conformation of helix-12 via a specific hydrogen-bond network including Glu(723). This interaction is absent when the full antagonist, RU486, binds to PR. Combined with a previously reported structure of Asoprisnil bound to the antagonist state of the receptor, this structure extends our understanding of the complex molecular interactions underlying the mixed agonist/antagonist profile of the compound. In addition, we present the structure of PR in its agonist conformation bound to the mixed profile compound Org3H whose reduced antagonistic activity and increased agonistic activity compared with reference antagonists is due to an induced fit around Trp(755), resulting in a decreased steric clash with Met(909) but inducing a new internal clash with Val(912) in helix-12. This structure also explains the previously published observation that 16α attachments to RU486 analogs induce mixed profiles by altering the binding of 11β substituents. Together these structures further our understanding of the steric and electrostatic factors that contribute to the function of steroid receptor modulators, providing valuable insight for future compound design.

Articles - 4a2j mentioned but not cited (6)

  1. Structural protein-ligand interaction fingerprints (SPLIF) for structure-based virtual screening: method and benchmark study. Da C, Kireev D. J Chem Inf Model 54 2555-2561 (2014)
  2. X-ray structures of progesterone receptor ligand binding domain in its agonist state reveal differing mechanisms for mixed profiles of 11β-substituted steroids. Lusher SJ, Raaijmakers HC, Vu-Pham D, Kazemier B, Bosch R, McGuire R, Azevedo R, Hamersma H, Dechering K, Oubrie A, van Duin M, de Vlieg J. J Biol Chem 287 20333-20343 (2012)
  3. Exploring Flexibility of Progesterone Receptor Ligand Binding Domain Using Molecular Dynamics. Zheng L, Lin VC, Mu Y. PLoS One 11 e0165824 (2016)
  4. An Assay on the Possible Effect of Essential Oil Constituents on Receptors Involved in Women's Hormonal Health and Reproductive System Diseases. Sakhteman A, Pasdaran A, Afifi M, Hamedi A. J Evid Based Integr Med 25 2515690X20932527 (2020)
  5. EC313-a tissue selective SPRM reduces the growth and proliferation of uterine fibroids in a human uterine fibroid tissue xenograft model. Nair HB, Santhamma B, Dileep KV, Binkley P, Acosta K, Zhang KYJ, Schenken R, Nickisch K. Sci Rep 9 17279 (2019)
  6. The Development of Target-Specific Pose Filter Ensembles To Boost Ligand Enrichment for Structure-Based Virtual Screening. Xia J, Hsieh JH, Hu H, Wu S, Wang XS. J Chem Inf Model 57 1414-1425 (2017)


Reviews citing this publication (4)

  1. Stabilization of protein-protein interactions in drug discovery. Andrei SA, Sijbesma E, Hann M, Davis J, O'Mahony G, Perry MWD, Karawajczyk A, Eickhoff J, Brunsveld L, Doveston RG, Milroy LG, Ottmann C. Expert Opin Drug Discov 12 925-940 (2017)
  2. Progesterone receptor targeting with radiolabelled steroids: an approach in predicting breast cancer response to therapy. Cunha S, Gano L, Morais GR, Thiemann T, Oliveira MC. J Steroid Biochem Mol Biol 137 223-241 (2013)
  3. Progestin therapy to prevent preterm birth: History and effectiveness of current strategies and development of novel approaches. Mesiano SA, Peters GA, Amini P, Wilson RA, Tochtrop GP, van Den Akker F. Placenta 79 46-52 (2019)
  4. Recent advances in structure of progestins and their binding to progesterone receptors. Cabeza M, Heuze Y, Sánchez A, Garrido M, Bratoeff E. J Enzyme Inhib Med Chem 30 152-159 (2015)

Articles citing this publication (9)

  1. Ligand induced dissociation of the AR homodimer precedes AR monomer translocation to the nucleus. Shizu R, Yokobori K, Perera L, Pedersen L, Negishi M. Sci Rep 9 16734 (2019)
  2. A new strategy for selective targeting of progesterone receptor with passive antagonists. Khan JA, Tikad A, Fay M, Hamze A, Fagart J, Chabbert-Buffet N, Meduri G, Amazit L, Brion JD, Alami M, Lombès M, Loosfelt H, Rafestin-Oblin ME. Mol Endocrinol 27 909-924 (2013)
  3. Triterpenes from Alisma orientalis act as androgen receptor agonists, progesterone receptor antagonists, and glucocorticoid receptor antagonists. Lin HR. Bioorg Med Chem Lett 24 3626-3632 (2014)
  4. Progesterone-targeted magnetic resonance imaging probes. Townsend TR, Moyle-Heyrman G, Sukerkar PA, MacRenaris KW, Burdette JE, Meade TJ. Bioconjug Chem 25 1428-1437 (2014)
  5. Structure-Based Drug Design of Mineralocorticoid Receptor Antagonists to Explore Oxosteroid Receptor Selectivity. Nordqvist A, O'Mahony G, Fridén-Saxin M, Fredenwall M, Hogner A, Granberg KL, Aagaard A, Bäckström S, Gunnarsson A, Kaminski T, Xue Y, Dellsén A, Hansson E, Hansson P, Ivarsson I, Karlsson U, Bamberg K, Hermansson M, Georgsson J, Lindmark B, Edman K. ChemMedChem 12 50-65 (2017)
  6. Ligand Binding Induces Agonistic-Like Conformational Adaptations in Helix 12 of Progesterone Receptor Ligand Binding Domain. Zheng L, Xia K, Mu Y. Front Chem 7 315 (2019)
  7. Functional Effects In Silico Prediction for Androgen Receptor Ligand-Binding Domain Novel I836S Mutation. Rayevsky A, Sirokha D, Samofalova D, Lozhko D, Gorodna O, Prokopenko I, Livshits L. Life (Basel) 11 659 (2021)
  8. Structural overview and perspectives of the nuclear receptors, a major family as the direct targets for small-molecule drugs. Li F, Song C, Zhang Y, Wu D. Acta Biochim Biophys Sin (Shanghai) 54 12-24 (2022)
  9. Identification of ELK1 interacting peptide segments in the androgen receptor. Soave C, Ducker C, Kim S, Strahl T, Rosati R, Huang Y, Shaw PE, Ratnam M. Biochem J 479 1519-1531 (2022)


Quick links