5l7h
From Proteopedia
MCR IN COMPLEX WITH ligand
Structural highlights
DiseaseMCR_HUMAN Defects in NR3C2 are a cause of pseudohypoaldosteronism 1, autosomal dominant (PHA1A) [MIM:177735. A salt wasting disease resulting from target organ unresponsiveness to mineralocorticoids. PHA1A is a mild form characterized by target organ defects confined to kidney. Patients may present with neonatal renal salt wasting with hyperkalaemic acidosis despite high aldosterone levels. These patients improve with age and usually become asymptomatic without treatment.[1] [2] [3] [4] [5] Defects in NR3C2 are a cause of early-onset hypertension with severe exacerbation in pregnancy (EOHSEP) [MIM:605115. Inheritance is autosomal dominant. The disease is characterized by the onset of severe hypertension before the age of 20, and by suppression of aldosterone secretion.[6] [7] [8] [9] FunctionMCR_HUMAN Receptor for both mineralocorticoids (MC) such as aldosterone and glucocorticoids (GC) such as corticosterone or cortisol. Binds to mineralocorticoid response elements (MRE) and transactivates target genes. The effect of MC is to increase ion and water transport and thus raise extracellular fluid volume and blood pressure and lower potassium levels.[10] Publication Abstract from PubMedThe mineralocorticoid receptor (MR) is a nuclear hormone receptor involved in regulation of body fluid and electrolyte homeostasis. In this study we explore selectivity triggers for a series of non-steroidal MR antagonists to improve selectivity over other members of the oxosteroid receptor family. A biaryl sulfonamide compound was identified in a high-throughput screening (HTS) campaign. The compound bound to MR with a pKi=6.6, but displayed poor selectivity over the glucocorticoid receptor (GR) and the progesterone receptor (PR). Following X-ray crystallography of MR in complex with the HTS hit, a compound library was designed that explored an induced fit hypothesis that required movement of the Met852 side-chain. An improvement in MR selectivity of 11-79 fold over PR and 23-234 fold over GR was obtained. Given the U-shaped binding conformation, macrocyclizations were explored yielding a macrocycle that bound to MR with a pKi=7.3. Two protein-ligand X-ray structures were determined confirming the hypothesized binding mode for the designed compounds. Structure-based drug design of mineralocorticoid receptor antagonists to explore oxosteroid receptor selectivity.,Nordqvist A, O'Mahony G, Friden-Saxin M, Fredenwall M, Hogner A, Granberg KL, Aagaard A, Backstrom S, Gunnarsson A, Kaminski T, Xue Y, Dellsen A, Hansson E, Hansson P, Ivarsson I, Karlsson U, Bamberg K, Hermansson M, Georgsson J, Lindmark B, Edman K ChemMedChem. 2016 Nov 29. doi: 10.1002/cmdc.201600529. PMID:27897427[11] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. Loading citation details.. Citations No citations found See AlsoReferences
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