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Crystal structure of a mutant hERalpha ligand-binding domain reveals key structural features for the mechanism of partial agonism.

Gangloff M, Ruff M, Eiler S, Duclaud S, Wurtz JM, Moras D
J Biol Chem 276 15059-65 (2001)
Cited: 85 times
EuropePMC logo PMID: 11278577

Abstract

The crystal structure of a triple cysteine to serine mutant ERalpha ligand-binding domain (LBD), complexed with estradiol, shows that despite the presence of a tightly bound agonist ligand, the protein exhibits an antagonist-like conformation, similar to that observed in raloxifen and 4-hydroxytamoxifen-bound structures. This mutated receptor binds estradiol with wild type affinity and displays transcriptional activity upon estradiol stimulation, but with limited potency (about 50%). This partial activity is efficiently repressed in antagonist competition assays. The comparison with available LBD structures reveals key features governing the positioning of helix H12 and highlights the importance of cysteine residues in promoting an active conformation. Furthermore the present study reveals a hydrogen bond network connecting ligand binding to protein trans conformation. These observations support a dynamic view of H12 positioning, where the control of the equilibrium between two stable locations determines the partial agonist character of a given ligand.

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  1. Visualization of macromolecular structures. O'Donoghue SI, Goodsell DS, Frangakis AS, Jossinet F, Laskowski RA, Nilges M, Saibil HR, Schafferhans A, Wade RC, Westhof E, Olson AJ. Nat. Methods 7 S42-55 (2010)
  2. Versatility or promiscuity: the estrogen receptors, control of ligand selectivity and an update on subtype selective ligands. Ng HW, Perkins R, Tong W, Hong H. Int J Environ Res Public Health 11 8709-8742 (2014)
  3. Structural underpinnings of oestrogen receptor mutations in endocrine therapy resistance. Katzenellenbogen JA, Mayne CG, Katzenellenbogen BS, Greene GL, Chandarlapaty S. Nat. Rev. Cancer 18 377-388 (2018)
  4. Computer-Aided Ligand Discovery for Estrogen Receptor Alpha. Bafna D, Ban F, Rennie PS, Singh K, Cherkasov A. Int J Mol Sci 21 (2020)
  5. Estrogen Receptor-α Targeting: PROTACs, SNIPERs, Peptide-PROTACs, Antibody Conjugated PROTACs and SNIPERs. Negi A, Kesari KK, Voisin-Chiret AS. Pharmaceutics 14 2523 (2022)

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  1. Novel aromatase inhibitors by structure-guided design. Ghosh D, Lo J, Morton D, Valette D, Xi J, Griswold J, Hubbell S, Egbuta C, Jiang W, An J, Davies HM. J. Med. Chem. 55 8464-8476 (2012)
  2. Ligand dissociation from estrogen receptor is mediated by receptor dimerization: evidence from molecular dynamics simulations. Sonoda MT, Martínez L, Webb P, Skaf MS, Polikarpov I. Mol. Endocrinol. 22 1565-1578 (2008)
  3. A Computational Assay of Estrogen Receptor α Antagonists Reveals the Key Common Structural Traits of Drugs Effectively Fighting Refractory Breast Cancers. Pavlin M, Spinello A, Pennati M, Zaffaroni N, Gobbi S, Bisi A, Colombo G, Magistrato A. Sci Rep 8 649 (2018)
  4. Consistent two-dimensional visualization of protein-ligand complex series. Stierand K, Rarey M. J Cheminform 3 21 (2011)
  5. An alternative conformation of ERβ bound to estradiol reveals H12 in a stable antagonist position. Souza PCT, Textor LC, Melo DC, Nascimento AS, Skaf MS, Polikarpov I. Sci Rep 7 3509 (2017)
  6. Computational study of evolutionary selection pressure on rainbow trout estrogen receptors. Shyu C, Brown CJ, Ytreberg FM. PLoS ONE 5 e9392 (2010)
  7. Nuclear receptor engineering based on novel structure activity relationships revealed by farnesyl pyrophosphate. Goyanka R, Das S, Samuels HH, Cardozo T. Protein Eng. Des. Sel. 23 809-815 (2010)
  8. The effect of protein mutations on drug binding suggests ensuing personalised drug selection. Wan S, Kumar D, Ilyin V, Al Homsi U, Sher G, Knuth A, Coveney PV. Sci Rep 11 13452 (2021)
  9. Chemical Composition and Biological Properties of Two Jatropha Species: Different Parts and Different Extraction Methods. Zengin G, Mahomoodally MF, Sinan KI, Ak G, Etienne OK, Sharmeen JB, Brunetti L, Leone S, Di Simone SC, Recinella L, Chiavaroli A, Menghini L, Orlando G, Jekő J, Cziáky Z, Ferrante C. Antioxidants (Basel) 10 792 (2021)
  10. Estrogen-Like Effect of Mitotane Explained by Its Agonist Activity on Estrogen Receptor-α. Rossini E, Giacopuzzi E, Gangemi F, Tamburello M, Cosentini D, Abate A, Laganà M, Berruti A, Grisanti S, Sigala S. Biomedicines 9 681 (2021)
  11. Molecular Basis for Endocrine Disruption by Pesticides Targeting Aromatase and Estrogen Receptor. Zhang C, Schilirò T, Gea M, Bianchi S, Spinello A, Magistrato A, Gilardi G, Di Nardo G. Int J Environ Res Public Health 17 (2020)
  12. Multidomain architecture of estrogen receptor reveals interfacial cross-talk between its DNA-binding and ligand-binding domains. Huang W, Peng Y, Kiselar J, Zhao X, Albaqami A, Mendez D, Chen Y, Chakravarthy S, Gupta S, Ralston C, Kao HY, Chance MR, Yang S. Nat Commun 9 3520 (2018)
  13. Alkyne-Tagged Apigenin, a Chemical Tool to Navigate Potential Targets of Flavonoid Anti-Dengue Leads. Hengphasatporn K, Kaewmalai B, Jansongsaeng S, Badavath VN, Saelee T, Chokmahasarn T, Khotavivattana T, Shigeta Y, Rungrotmongkol T, Boonyasuppayakorn S. Molecules 26 6967 (2021)
  14. Bisphenol A derivatives act as novel coactivator-binding inhibitors for estrogen receptor β. Iwamoto M, Masuya T, Hosose M, Tagawa K, Ishibashi T, Suyama K, Nose T, Yoshihara E, Downes M, Evans RM, Matsushima A. J Biol Chem 297 101173 (2021)
  15. Evidence that nuclear receptors are related to terpene synthases. Houston DR, Hanna JG, Lathe JC, Hillier SG, Lathe R. J Mol Endocrinol 68 153-166 (2022)
  16. Human Growth Hormone Fragment 176-191 Peptide Enhances the Toxicity of Doxorubicin-Loaded Chitosan Nanoparticles Against MCF-7 Breast Cancer Cells. Habibullah MM, Mohan S, Syed NK, Makeen HA, Jamal QMS, Alothaid H, Bantun F, Alhazmi A, Hakamy A, Kaabi YA, Samlan G, Lohani M, Thangavel N, Al-Kasim MA. Drug Des Devel Ther 16 1963-1974 (2022)
  17. Middle-way flexible docking: Pose prediction using mixed-resolution Monte Carlo in estrogen receptor α. Spiriti J, Subramanian SR, Palli R, Wu M, Zuckerman DM. PLoS ONE 14 e0215694 (2019)
  18. Neutrophil Immunomodulatory Activity of Nerolidol, a Major Component of Essential Oils from Populus balsamifera Buds and Propolis. Schepetkin IA, Özek G, Özek T, Kirpotina LN, Kokorina PI, Khlebnikov AI, Quinn MT. Plants (Basel) 11 3399 (2022)
  19. Predicting Potential Endocrine Disrupting Chemicals Binding to Estrogen Receptor α (ERα) Using a Pipeline Combining Structure-Based and Ligand-Based in Silico Methods. Sellami A, Montes M, Lagarde N. Int J Mol Sci 22 2846 (2021)
  20. Protein Conformational Transitions from All-Atom Adaptively Biased Path Optimization. Wu H, Post CB. J Chem Theory Comput 14 5372-5382 (2018)
  21. The Mechanism and Experimental Validation of Forsythoside A in the Treatment of Male Infertility Were Analyzed Based on Network Pharmacology and Molecular Docking. Ma Z, Liu X, Lu H, Li H, Gao R, Wen R, Tang Z, Yin H, He Y, Yang H. Evid Based Complement Alternat Med 2022 7723358 (2022)


Reviews citing this publication (11)

  1. Estrogen receptors: how do they signal and what are their targets. Heldring N, Pike A, Andersson S, Matthews J, Cheng G, Hartman J, Tujague M, Ström A, Treuter E, Warner M, Gustafsson JA. Physiol. Rev. 87 905-931 (2007)
  2. Structure-function relationship of estrogen receptor alpha and beta: impact on human health. Ascenzi P, Bocedi A, Marino M. Mol. Aspects Med. 27 299-402 (2006)
  3. Reflections on the discovery and significance of estrogen receptor beta. Koehler KF, Helguero LA, Haldosén LA, Warner M, Gustafsson JA. Endocr Rev 26 465-478 (2005)
  4. Structural overview of the nuclear receptor superfamily: insights into physiology and therapeutics. Huang P, Chandra V, Rastinejad F. Annu. Rev. Physiol. 72 247-272 (2010)
  5. The glucocorticoid receptor: coding a diversity of proteins and responses through a single gene. Yudt MR, Cidlowski JA. Mol Endocrinol 16 1719-1726 (2002)
  6. Estrogen and progesterone receptors: from molecular structures to clinical targets. Ellmann S, Sticht H, Thiel F, Beckmann MW, Strick R, Strissel PL. Cell. Mol. Life Sci. 66 2405-2426 (2009)
  7. Lessons learnt from structural studies of the oestrogen receptor. Pike AC. Best Pract. Res. Clin. Endocrinol. Metab. 20 1-14 (2006)
  8. Membrane and Nuclear Estrogen Receptor Alpha Actions: From Tissue Specificity to Medical Implications. Arnal JF, Lenfant F, Metivier R, Flouriot G, Henrion D, Adlanmerini M, Fontaine C, Gourdy P, Chambon P, Katzenellenbogen B, Katzenellenbogen J. Physiol. Rev. 97 1045-1087 (2017)
  9. Different ligands-different receptor conformations: modeling of the hER alpha LBD in complex with agonists and antagonists. Egner U, Heinrich N, Ruff M, Gangloff M, Mueller-Fahrnow A, Wurtz JM. Med Res Rev 21 523-539 (2001)
  10. Targeting the androgen receptor with steroid conjugates. Levine PM, Garabedian MJ, Kirshenbaum K. J. Med. Chem. 57 8224-8237 (2014)
  11. Transactivation Function-1-Mediated Partial Agonist Activity of Selective Estrogen Receptor Modulator Requires Homo-Dimerization of the Estrogen Receptor α Ligand Binding Domain. Arao Y, Korach KS. Int J Mol Sci 20 (2019)

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  1. Multiple hormonal activities of UV filters and comparison of in vivo and in vitro estrogenic activity of ethyl-4-aminobenzoate in fish. Kunz PY, Fent K. Aquat. Toxicol. 79 305-324 (2006)
  2. Crystal structure of the 2'-specific and double-stranded RNA-activated interferon-induced antiviral protein 2'-5'-oligoadenylate synthetase. Hartmann R, Justesen J, Sarkar SN, Sen GC, Yee VC. Mol. Cell 12 1173-1185 (2003)
  3. Kinetic analysis of estrogen receptor/ligand interactions. Rich RL, Hoth LR, Geoghegan KF, Brown TA, LeMotte PK, Simons SP, Hensley P, Myszka DG. Proc. Natl. Acad. Sci. U.S.A. 99 8562-8567 (2002)
  4. X-ray structure of the orphan nuclear receptor RORbeta ligand-binding domain in the active conformation. Stehlin C, Wurtz JM, Steinmetz A, Greiner E, Schüle R, Moras D, Renaud JP. EMBO J. 20 5822-5831 (2001)
  5. One-step site-specific modification of native proteins with 2-pyridinecarboxyaldehydes. MacDonald JI, Munch HK, Moore T, Francis MB. Nat. Chem. Biol. 11 326-331 (2015)
  6. Estrogen receptor alpha somatic mutations Y537S and D538G confer breast cancer endocrine resistance by stabilizing the activating function-2 binding conformation. Fanning SW, Mayne CG, Dharmarajan V, Carlson KE, Martin TA, Novick SJ, Toy W, Green B, Panchamukhi S, Katzenellenbogen BS, Tajkhorshid E, Griffin PR, Shen Y, Chandarlapaty S, Katzenellenbogen JA, Greene GL. Elife 5 (2016)
  7. Ligands differentially modulate the protein interactions of the human estrogen receptors alpha and beta. Margeat E, Bourdoncle A, Margueron R, Poujol N, Cavaillès V, Royer C. J. Mol. Biol. 326 77-92 (2003)
  8. A second binding site for hydroxytamoxifen within the coactivator-binding groove of estrogen receptor beta. Wang Y, Chirgadze NY, Briggs SL, Khan S, Jensen EV, Burris TP. Proc. Natl. Acad. Sci. U.S.A. 103 9908-9911 (2006)
  9. Identification of a potent synthetic FXR agonist with an unexpected mode of binding and activation. Soisson SM, Parthasarathy G, Adams AD, Sahoo S, Sitlani A, Sparrow C, Cui J, Becker JW. Proc. Natl. Acad. Sci. U.S.A. 105 5337-5342 (2008)
  10. Ab initio quantum mechanical study of the binding energies of human estrogen receptor alpha with its ligands: an application of fragment molecular orbital method. Fukuzawa K, Kitaura K, Uebayasi M, Nakata K, Kaminuma T, Nakano T. J Comput Chem 26 1-10 (2005)
  11. Binding of estrogenic compounds to recombinant estrogen receptor-alpha: application to environmental analysis. Pillon A, Boussioux AM, Escande A, Aït-Aïssa S, Gomez E, Fenet H, Ruff M, Moras D, Vignon F, Duchesne MJ, Casellas C, Nicolas JC, Balaguer P. Environ. Health Perspect. 113 278-284 (2005)
  12. Overexpression, purification, and crystal structure of native ER alpha LBD. Eiler S, Gangloff M, Duclaud S, Moras D, Ruff M. Protein Expr. Purif. 22 165-173 (2001)
  13. Isotype-restricted corepressor recruitment: a constitutively closed helix 12 conformation in retinoic acid receptors beta and gamma interferes with corepressor recruitment and prevents transcriptional repression. Farboud B, Hauksdottir H, Wu Y, Privalsky ML. Mol. Cell. Biol. 23 2844-2858 (2003)
  14. A new class of phytoestrogens; evaluation of the estrogenic activity of deoxybenzoins. Fokialakis N, Lambrinidis G, Mitsiou DJ, Aligiannis N, Mitakou S, Skaltsounis AL, Pratsinis H, Mikros E, Alexis MN. Chem. Biol. 11 397-406 (2004)
  15. Consensus Induced Fit Docking (cIFD): methodology, validation, and application to the discovery of novel Crm1 inhibitors. Kalid O, Toledo Warshaviak D, Shechter S, Sherman W, Shacham S. J. Comput. Aided Mol. Des. 26 1217-1228 (2012)
  16. Design novel dual agonists for treating type-2 diabetes by targeting peroxisome proliferator-activated receptors with core hopping approach. Ma Y, Wang SQ, Xu WR, Wang RL, Chou KC. PLoS ONE 7 e38546 (2012)
  17. Estrogen receptor-ligand complexes measured by chip-based nanoelectrospray mass spectrometry: an approach for the screening of endocrine disruptors. Bovet C, Wortmann A, Eiler S, Granger F, Ruff M, Gerrits B, Moras D, Zenobi R. Protein Sci. 16 938-946 (2007)
  18. Ubiquitin-interaction motifs of RAP80 are critical in its regulation of estrogen receptor alpha. Yan J, Kim YS, Yang XP, Albers M, Koegl M, Jetten AM. Nucleic Acids Res. 35 1673-1686 (2007)
  19. Characterisation of bioactive compounds in infant formulas using immobilised recombinant estrogen receptor-alpha affinity columns. Riu A, Balaguer P, Perdu E, Pandelova M, Piccinelli R, Gustafsson JA, Leclercq C, Schramm KW, Dagnino S, Debrauwer L, Cravedi JP, Zalko D. Food Chem. Toxicol. 46 3268-3278 (2008)
  20. A novel pesticide-induced conformational state of the oestrogen receptor ligand-binding domain, detected by conformation-specific peptide binding. Sumbayev VV, Bonefeld-Jørgensen EC, Wind T, Andreasen PA. FEBS Lett. 579 541-548 (2005)
  21. Competitive molecular docking approach for predicting estrogen receptor subtype α agonists and antagonists. Ng HW, Zhang W, Shu M, Luo H, Ge W, Perkins R, Tong W, Hong H. BMC Bioinformatics 15 Suppl 11 S4 (2014)
  22. Helix 11 dynamics is critical for constitutive androstane receptor activity. Wright E, Busby SA, Wisecarver S, Vincent J, Griffin PR, Fernandez EJ. Structure 19 37-44 (2011)
  23. An estrogen receptor chimera senses ligands by nuclear translocation. Martinez ED, Rayasam GV, Dull AB, Walker DA, Hager GL. J. Steroid Biochem. Mol. Biol. 97 307-321 (2005)
  24. Structure of estradiol metal chelate and estrogen receptor complex: the basis for designing a new class of selective estrogen receptor modulators. Li MJ, Greenblatt HM, Dym O, Albeck S, Pais A, Gunanathan C, Milstein D, Degani H, Sussman JL. J. Med. Chem. 54 3575-3580 (2011)
  25. Structure-dependent activities of hydroxylated polybrominated diphenyl ethers on human estrogen receptor. Li X, Gao Y, Guo LH, Jiang G. Toxicology 309 15-22 (2013)
  26. Glucocorticoid receptor point mutation V571M facilitates coactivator and ligand binding by structural rearrangement and stabilization. Carlsson P, Koehler KF, Nilsson L. Mol Endocrinol 19 1960-1977 (2005)
  27. Quantitative structure activity relationship (QSAR) study of estrogen derivatives based on descriptors of energy and softness. Pasha FA, Neaz MM, Cho SJ, Kang SB. Chem Biol Drug Des 70 520-529 (2007)
  28. Cross-talk between the ligand- and DNA-binding domains of estrogen receptor. Huang W, Greene GL, Ravikumar KM, Yang S. Proteins 81 1900-1909 (2013)
  29. LIBSA--a method for the determination of ligand-binding preference to allosteric sites on receptor ensembles. Hocker HJ, Rambahal N, Gorfe AA. J Chem Inf Model 54 530-538 (2014)
  30. Differential estrogen receptor subtype modulators: assessment of estrogen receptor subtype-binding selectivity and transcription-regulating properties of new cycloalkyl pyrazoles. Alexi X, Kasiotis KM, Fokialakis N, Lambrinidis G, Meligova AK, Mikros E, Haroutounian SA, Alexis MN. J. Steroid Biochem. Mol. Biol. 117 159-167 (2009)
  31. Activation helix orientation of the estrogen receptor is mediated by receptor dimerization: evidence from molecular dynamics simulations. Fratev F. Phys Chem Chem Phys 17 13403-13420 (2015)
  32. Local motifs involved in the canonical structure of the ligand-binding domain in the nuclear receptor superfamily. Tsuji M. J. Struct. Biol. 185 355-365 (2014)
  33. Towards high-throughput identification of endocrine disrupting compounds with mass spectrometry. Bovet C, Plet B, Ruff M, Eiler S, Granger F, Panagiotidis A, Wenzel R, Nazabal A, Moras D, Zenobi R. Toxicol In Vitro 23 704-709 (2009)
  34. The N-terminal adenosine triphosphate binding domain of Hsp90 is necessary and sufficient for interaction with estrogen receptor. Bouhouche-Chatelier L, Chadli A, Catelli MG. Cell Stress Chaperones 6 297-305 (2001)
  35. Cleaved thioredoxin fusion protein enables the crystallization of poorly soluble ERalpha in complex with synthetic ligands. Cura V, Gangloff M, Eiler S, Moras D, Ruff M. Acta Crystallogr Sect F Struct Biol Cryst Commun 64 54-57 (2008)
  36. Combination of receptor-binding assays and designed mutant receptors for discerning agonists and antagonists. Matsui K. J Pharm Biomed Anal 43 822-828 (2007)
  37. Deoxybenzoins are novel potent selective estrogen receptor modulators. Papoutsi Z, Kassi E, Fokialakis N, Mitakou S, Lambrinidis G, Mikros E, Moutsatsou P. Steroids 72 693-704 (2007)
  38. Potential activity of fevicordin-A from Phaleria macrocarpa (Scheff) Boerl. seeds as estrogen receptor antagonist based on cytotoxicity and molecular modelling studies. Muchtaridi M, Yusuf M, Diantini A, Choi SB, Al-Najjar BO, Manurung JV, Subarnas A, Achmad TH, Wardhani SR, Wahab HA. Int J Mol Sci 15 7225-7249 (2014)
  39. Hydrogen peroxide induced activation of gene expression in mammalian cells using boronate estrone derivatives. Govan JM, McIver AL, Riggsbee C, Deiters A. Angew. Chem. Int. Ed. Engl. 51 9066-9070 (2012)
  40. Exploring the molecular basis of action of ring D aromatic steroidal antiestrogens. Alvarez LD, Veleiro AS, Burton G. Proteins 83 1297-1306 (2015)
  41. Mass spectrometry identification of covalent attachment sites of two related estrogenic ligands on human estrogen receptor alpha. Mattras H, Aliau S, Demey E, Poncet J, Borgna JL. J. Steroid Biochem. Mol. Biol. 98 236-247 (2006)
  42. Production of unstable proteins through the formation of stable core complexes. Levy N, Eiler S, Pradeau-Aubreton K, Maillot B, Stricher F, Ruff M. Nat Commun 7 10932 (2016)
  43. Targeted mutation of key residues at the start of helix 12 in the hERalpha ligand-binding domain identifies the role of hydrogen-bonding and hydrophobic interactions in the activity of the protein. Zhao C, Abrams J, Skafar DF. J. Steroid Biochem. Mol. Biol. 98 1-11 (2006)
  44. Exploring the Anticancer Activity of Tamoxifen-Based Metal Complexes Targeting Mitochondria. Scalcon V, Bonsignore R, Aupič J, Thomas SR, Folda A, Heidecker AA, Pöthig A, Magistrato A, Casini A, Rigobello MP. J Med Chem 66 9823-9841 (2023)
  45. Comment Fast-tracking steroid receptor crystallization. Mader S. Nat. Chem. Biol. 4 226-227 (2008)
  46. Human Estrogen Receptor Alpha Antagonists, Part 3: 3-D Pharmacophore and 3-D QSAR Guided Brefeldin A Hit-to-Lead Optimization toward New Breast Cancer Suppressants. Kurtanović N, Tomašević N, Matić S, Proia E, Sabatino M, Antonini L, Mladenović M, Ragno R. Molecules 27 2823 (2022)
  47. Novel Carbonyl Analogs of Tamoxifen: Design, Synthesis, and Biological Evaluation. Kasiotis KM, Lambrinidis G, Fokialakis N, Tzanetou EN, Mikros E, Haroutounian SA. Front Chem 5 71 (2017)
  48. Synthesis, Biological Activity, ADME and Molecular Docking Studies of Novel Ursolic Acid Derivatives as Potent Anticancer Agents. Michalak O, Cybulski M, Szymanowski W, Gornowicz A, Kubiszewski M, Ostrowska K, Krzeczyński P, Bielawski K, Trzaskowski B, Bielawska A. Int J Mol Sci 24 8875 (2023)


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