1m2z
From Proteopedia
Crystal structure of a dimer complex of the human glucocorticoid receptor ligand-binding domain bound to dexamethasone and a TIF2 coactivator motif
Structural highlights
Disease[GCR_HUMAN] Defects in NR3C1 are a cause of glucocorticoid resistance (GCRES) [MIM:138040]; also known as cortisol resistance. It is a hypertensive, hyperandrogenic disorder characterized by increased serum cortisol concentrations. Inheritance is autosomal dominant.[1] [2] [3] [4] [5] [NCOA2_HUMAN] Note=Chromosomal aberrations involving NCOA2 may be a cause of acute myeloid leukemias. Inversion inv(8)(p11;q13) generates the KAT6A-NCOA2 oncogene, which consists of the N-terminal part of KAT6A and the C-terminal part of NCOA2/TIF2. KAT6A-NCOA2 binds to CREBBP and disrupts its function in transcription activation. Function[GCR_HUMAN] Receptor for glucocorticoids (GC). Has a dual mode of action: as a transcription factor that binds to glucocorticoid response elements (GRE), both for nuclear and mitochondrial DNA, and as a modulator of other transcription factors. Affects inflammatory responses, cellular proliferation and differentiation in target tissues. Could act as a coactivator for STAT5-dependent transcription upon growth hormone (GH) stimulation and could reveal an essential role of hepatic GR in the control of body growth. Involved in chromatin remodeling. Plays a significant role in transactivation.[6] [NCOA2_HUMAN] Transcriptional coactivator for steroid receptors and nuclear receptors. Coactivator of the steroid binding domain (AF-2) but not of the modulating N-terminal domain (AF-1). Required with NCOA1 to control energy balance between white and brown adipose tissues.[7] Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMedTranscriptional regulation by the glucocorticoid receptor (GR) is mediated by hormone binding, receptor dimerization, and coactivator recruitment. Here, we report the crystal structure of the human GR ligand binding domain (LBD) bound to dexamethasone and a coactivator motif derived from the transcriptional intermediary factor 2. Despite structural similarity to other steroid receptors, the GR LBD adopts a surprising dimer configuration involving formation of an intermolecular beta sheet. Functional studies demonstrate that the novel dimer interface is important for GR-mediated activation. The structure also reveals an additional charge clamp that determines the binding selectivity of a coactivator and a distinct ligand binding pocket that explains its selectivity for endogenous steroid hormones. These results establish a framework for understanding the roles of protein-hormone and protein-protein interactions in GR signaling pathways. Crystal structure of the glucocorticoid receptor ligand binding domain reveals a novel mode of receptor dimerization and coactivator recognition.,Bledsoe RK, Montana VG, Stanley TB, Delves CJ, Apolito CJ, McKee DD, Consler TG, Parks DJ, Stewart EL, Willson TM, Lambert MH, Moore JT, Pearce KH, Xu HE Cell. 2002 Jul 12;110(1):93-105. PMID:12151000[8] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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Categories: Human | Large Structures | Apolito, C J | Bledsoe, R B | Consler, T G | Delves, C J | Lambert, M H | Mckee, D D | Montana, V G | Moore, J T | Parks, D J | Pearce, K H | Stanley, T B | Stewart, E L | Willson, T M | Xu, H E | Charge clamp | Coactivator | Dexamethasone | Dimer interface | Glucocorticoid receptor | Hormone binding pocket | Hormone-hormone activator complex | Tif2
