5L7E

MCR IN COMPLEX WITH ligand

Summary for 5L7E

• Entry DOI: 10.2210/pdb5l7e/pdb
• Descriptor: Mineralocorticoid receptor, NCOA1 peptide, 2-[N-CYCLOHEXYLAMINO]ETHANE SULFONIC ACID, ... (8 entities in total)
• Functional Keywords: mineralocorticoid receptor 2, signaling protein
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 2
• Total formula weight: 36894.21

Authors

Edman, K.,Aagaard, A.,Backstrom, S.,Xue, Y. (deposition date: 2016-06-03, release date: 2016-12-07, Last modification date: 2024-05-08)

Primary citation

Nordqvist, A.,O'Mahony, G.,Friden-Saxin, M.,Fredenwall, M.,Hogner, A.,Granberg, K.L.,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.
Structure-Based Drug Design of Mineralocorticoid Receptor Antagonists to Explore Oxosteroid Receptor Selectivity.
ChemMedChem, 12:50-65, 2017

PubMed Abstract: The mineralocorticoid receptor (MR) is a nuclear hormone receptor involved in the regulation of body fluid and electrolyte homeostasis. In this study we explore selectivity triggers for a series of nonsteroidal 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 pK =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- to 79-fold over PR and 23- to 234-fold over GR was obtained. Given the U-shaped binding conformation, macrocyclizations were explored, yielding a macrocycle that bound to MR with pK =7.3. Two protein-ligand X-ray structures were determined, confirming the hypothesized binding mode for the designed compounds.

PubMed: 27897427
DOI: 10.1002/cmdc.201600529

Experimental method

X-RAY DIFFRACTION (1.86 Å)