PDBsum entry 4djh

Hormone receptor/antagonist

PDB id: 4djh

Contents

Protein chain

447 a.a.

Ligands

JDC ×2

CIT

OLC ×2

PEG ×2

Waters ×25

PDB id:

4djh

Name:

Hormone receptor/antagonist

Title:

Structure of the human kappa opioid receptor in complex with jdtic

Structure:

Kappa-type opioid receptor, lysozyme. Chain: a, b. Fragment: unp p41145 residues 43-261, unp p00720 residues 2-161, unp p41145 residues 362-358. Synonym: k-or-1, kor-1. Engineered: yes. Mutation: yes

Source:

Homo sapiens, enterobacteria phage t4. Human, bacteriophage t4. Organism_taxid: 9606, 10665. Gene: oprk, oprk1, oprk, e. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108.

Resolution:

2.90Å R-factor: 0.229 R-free: 0.265

Authors:

H.Wu,D.Wacker,V.Katritch,M.Mileni,G.W.Han,E.Vardy,W.Liu,A.A.Thompson, X.P.Huang,F.I.Carroll,S.W.Mascarella,R.B.Westkaemper,P.D.Mosier, B.L.Roth,V.Cherezov,R.C.Stevens,Gpcr Network (Gpcr)

Key ref:

H.Wu et al. (2012). Structure of the human κ-opioid receptor in complex with JDTic. Nature, 485, 327-332. PubMed id: 22437504 DOI: 10.1038/nature10939

Date:

01-Feb-12 Release date: 21-Mar-12

Protein chains

P00720  (ENLYS_BPT4) -  Endolysin from Enterobacteria phage T4

Seq: 164 a.a.

Struc: 447 a.a.*

Protein chains

P41145  (OPRK_HUMAN) -  Kappa-type opioid receptor from Homo sapiens

Seq: 380 a.a.

Struc: 447 a.a.*

* PDB and UniProt seqs differ at 169 residue positions (black crosses)

Enzyme reactions

• Enzyme class: E.C.3.2.1.17 - lysozyme.
• Reaction: Hydrolysis of the 1,4-beta-linkages between N-acetyl-D-glucosamine and N-acetylmuramic acid in peptidoglycan heteropolymers of the prokaryotes cell walls.

DOI no: 10.1038/nature10939

Nature 485:327-332 (2012)

PubMed id: 22437504

Structure of the human κ-opioid receptor in complex with JDTic.

H.Wu, D.Wacker, M.Mileni, V.Katritch, G.W.Han, E.Vardy, W.Liu, A.A.Thompson, X.P.Huang, F.I.Carroll, S.W.Mascarella, R.B.Westkaemper, P.D.Mosier, B.L.Roth, V.Cherezov, R.C.Stevens.

ABSTRACT

Opioid receptors mediate the actions of endogenous and exogenous opioids on many physiological processes, including the regulation of pain, respiratory drive, mood, and--in the case of κ-opioid receptor (κ-OR)--dysphoria and psychotomimesis. Here we report the crystal structure of the human κ-OR in complex with the selective antagonist JDTic, arranged in parallel dimers, at 2.9 Å resolution. The structure reveals important features of the ligand-binding pocket that contribute to the high affinity and subtype selectivity of JDTic for the human κ-OR. Modelling of other important κ-OR-selective ligands, including the morphinan-derived antagonists norbinaltorphimine and 5'-guanidinonaltrindole, and the diterpene agonist salvinorin A analogue RB-64, reveals both common and distinct features for binding these diverse chemotypes. Analysis of site-directed mutagenesis and ligand structure-activity relationships confirms the interactions observed in the crystal structure, thereby providing a molecular explanation for κ-OR subtype selectivity, and essential insights for the design of compounds with new pharmacological properties targeting the human κ-OR.

Selected figure(s)

Figure 3.
Putative interaction modes of morphine-based high-affinity [kgr]-OR-selective antagonists nor-BNI and GNTI.
a, b, Interaction modes of nor-BNI (a) and GNTI (b). Ligands are depicted as capped sticks with green carbons, and contact side chains of the receptor within 4 Å from the ligand are shown with grey carbons. Key hydrogen bonds and salt bridges are indicated with small cyan spheres and residues unique to the κ-OR are labelled in blue. Residue Asp 138^3.32, which also shows critical impact on GNTI and nor-BNI binding in mutagenesis studies, is highlighted in red. Ballesteros–Weinstein residue numbers are shown under the κ-OR residue numbers. The graphics were prepared using the ICM molecular modelling package (Molsoft LLC).

Figure 4.
Model of covalently bound RB-64.
a, b, Putative binding mode of the RB-64 +463 amu (a) and the RB-64 +431 amu (b) adduct. Residues within 4 Å of the ligand are shown. Ligand, capped sticks/cyan carbons; κ-OR side chains, capped sticks; hydrogen bonds, small green spheres; κ-OR-unique residues are labelled in blue. Ballesteros–Weinstein residue numbers are shown under the κ-OR residue numbers. The graphics were prepared using the ICM molecular modelling package (Molsoft LLC).

The above figures are reprinted from an Open Access publication published by Macmillan Publishers Ltd: Nature (2012, 485, 327-332) copyright 2012.

Figures were selected by an automated process.