PDBsum entry 4udb

Signaling protein

PDB id: 4udb

Contents

Protein chains

244 a.a.

12 a.a.

Ligands

DMS

GOL

SO4

CV7

Waters ×60

PDB id:

4udb

Name:

Signaling protein

Title:

Mr in complex with desisobutyrylciclesonide

Structure:

Mineralocorticoid receptor. Chain: a. Fragment: ligand binding domain, residues 735-984. Synonym: mr, nuclear receptor subfamily 3 group c member 2. Engineered: yes. Mutation: yes. Nuclear receptor coactivator 1. Chain: b. Fragment: residues 1427-1441.

Source:

Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 511693.

Resolution:

2.36Å R-factor: 0.184 R-free: 0.218

Authors:

K.Edman,A.Hogner,A.Hussein,A.Aagaard,S.Backstrom,C.Bodin,L.Wissler, T.Jellesmarkjensen,A.Cavallin,E.Nilsson,M.Lepisto,V.Guallar

Key ref:

K.Edman et al. (2015). Ligand Binding Mechanism in Steroid Receptors: From Conserved Plasticity to Differential Evolutionary Constraints. Structure, 23, 2280-2290. PubMed id: 26602186 DOI: 10.1016/j.str.2015.09.012

Date:

09-Dec-14 Release date: 25-Nov-15

Protein chain

P08235  (MCR_HUMAN) -  Mineralocorticoid receptor from Homo sapiens

Seq: 984 a.a.

Struc: 244 a.a.*

Protein chain

Q15788  (NCOA1_HUMAN) -  Nuclear receptor coactivator 1 from Homo sapiens

Seq: 1441 a.a.

Struc: 12 a.a.

* PDB and UniProt seqs differ at 3 residue positions (black crosses)

Enzyme reactions

• Enzyme class: Chain B: E.C.2.3.1.48 - histone acetyltransferase.
• Reaction: L-lysyl-[protein] + acetyl-CoA = N₆-acetyl-L-lysyl-[protein] + CoA + H⁺

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

Added reference

DOI no: 10.1016/j.str.2015.09.012

Structure 23:2280-2290 (2015)

PubMed id: 26602186

Ligand Binding Mechanism in Steroid Receptors: From Conserved Plasticity to Differential Evolutionary Constraints.

K.Edman, A.Hosseini, M.K.Bjursell, A.Aagaard, L.Wissler, A.Gunnarsson, T.Kaminski, C.Köhler, S.Bäckström, T.J.Jensen, A.Cavallin, U.Karlsson, E.Nilsson, D.Lecina, R.Takahashi, C.Grebner, S.Geschwindner, M.Lepistö, A.C.Hogner, V.Guallar.

ABSTRACT

Steroid receptor drugs have been available for more than half a century, but details of the ligand binding mechanism have remained elusive. We solved X-ray structures of the glucocorticoid and mineralocorticoid receptors to identify a conserved plasticity at the helix 6-7 region that extends the ligand binding pocket toward the receptor surface. Since none of the endogenous ligands exploit this region, we hypothesized that it constitutes an integral part of the binding event. Extensive all-atom unbiased ligand exit and entrance simulations corroborate a ligand binding pathway that gives the observed structural plasticity a key functional role. Kinetic measurements reveal that the receptor residence time correlates with structural rearrangements observed in both structures and simulations. Ultimately, our findings reveal why nature has conserved the capacity to open up this region, and highlight how differences in the details of the ligand entry process result in differential evolutionary constraints across the steroid receptors.