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Structural and biochemical mechanisms for the specificity of hormone binding and coactivator assembly by mineralocorticoid receptor.
Mol Cell. 2005 Aug 05; 19(3):367-80.MC

Abstract

Mineralocorticoid receptor (MR) controls sodium homeostasis and blood pressure through hormone binding and coactivator recruitment. Here, we report a 1.95 A crystal structure of the MR ligand binding domain containing a single C808S mutation bound to corticosterone and the fourth LXXLL motif of steroid receptor coactivator-1 (SRC1-4). Through a combination of biochemical and structural analyses, we demonstrate that SRC1-4 is the most potent MR binding motif and mutations that disrupt the MR/SRC1-4 interactions abolish the ability of the full-length SRC1 to coactivate MR. The structure also reveals a compact steroid binding pocket with a unique topology that is primarily defined by key residues of helices 6 and 7. Mutations swapping a single residue at position 848 from helix H7 between MR and glucocorticoid receptor (GR) switch their hormone specificity. Together, these findings provide critical insights into the molecular basis of hormone binding and coactivator recognition by MR and related steroid receptors.

Authors+Show Affiliations

Laboratory of Structural Sciences, Van Andel Research Institute, 333 Bostwick Avenue, Grand Rapids, Michigan 49503, USA.No affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

16061183

Citation

Li, Yong, et al. "Structural and Biochemical Mechanisms for the Specificity of Hormone Binding and Coactivator Assembly By Mineralocorticoid Receptor." Molecular Cell, vol. 19, no. 3, 2005, pp. 367-80.
Li Y, Suino K, Daugherty J, et al. Structural and biochemical mechanisms for the specificity of hormone binding and coactivator assembly by mineralocorticoid receptor. Mol Cell. 2005;19(3):367-80.
Li, Y., Suino, K., Daugherty, J., & Xu, H. E. (2005). Structural and biochemical mechanisms for the specificity of hormone binding and coactivator assembly by mineralocorticoid receptor. Molecular Cell, 19(3), 367-80.
Li Y, et al. Structural and Biochemical Mechanisms for the Specificity of Hormone Binding and Coactivator Assembly By Mineralocorticoid Receptor. Mol Cell. 2005 Aug 5;19(3):367-80. PubMed PMID: 16061183.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Structural and biochemical mechanisms for the specificity of hormone binding and coactivator assembly by mineralocorticoid receptor. AU - Li,Yong, AU - Suino,Kelly, AU - Daugherty,Jennifer, AU - Xu,H Eric, PY - 2005/04/05/received PY - 2005/05/31/revised PY - 2005/06/28/accepted PY - 2005/8/3/pubmed PY - 2005/11/3/medline PY - 2005/8/3/entrez SP - 367 EP - 80 JF - Molecular cell JO - Mol Cell VL - 19 IS - 3 N2 - Mineralocorticoid receptor (MR) controls sodium homeostasis and blood pressure through hormone binding and coactivator recruitment. Here, we report a 1.95 A crystal structure of the MR ligand binding domain containing a single C808S mutation bound to corticosterone and the fourth LXXLL motif of steroid receptor coactivator-1 (SRC1-4). Through a combination of biochemical and structural analyses, we demonstrate that SRC1-4 is the most potent MR binding motif and mutations that disrupt the MR/SRC1-4 interactions abolish the ability of the full-length SRC1 to coactivate MR. The structure also reveals a compact steroid binding pocket with a unique topology that is primarily defined by key residues of helices 6 and 7. Mutations swapping a single residue at position 848 from helix H7 between MR and glucocorticoid receptor (GR) switch their hormone specificity. Together, these findings provide critical insights into the molecular basis of hormone binding and coactivator recognition by MR and related steroid receptors. SN - 1097-2765 UR - https://www.unboundmedicine.com/medline/citation/16061183/Structural_and_biochemical_mechanisms_for_the_specificity_of_hormone_binding_and_coactivator_assembly_by_mineralocorticoid_receptor_ DB - PRIME DP - Unbound Medicine ER -