PDBsum entry 6ffh

Membrane protein

PDB id: 6ffh

Contents

Protein chain

414 a.a.

Ligands

OLA ×5

MES

D7W

OLC

Waters ×13

PDB id:

6ffh

Name:

Membrane protein

Title:

Crystal structure of mglur5 in complex with fenobam at 2.65 a

Structure:

Metabotropic glutamate receptor 5,endolysin. Chain: a. Fragment: mglur5. Synonym: mglur5,lysis protein,lysozyme,muramidase. Engineered: yes. Mutation: yes. Other_details: chimeric construct of human mglu5 (grm5) with a bacteriophage t4 lysozyme (p00720) insertion in intracellular loop 2 between residues lys678 and lys679.

Source:

Homo sapiens, enterobacteria phage t4. Human, bacteriophage t4. Organism_taxid: 9606, 10665. Gene: grm5, gprc1e, mglur5. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108. Expression_system_cell_line: sf21.

Resolution:

2.65Å R-factor: 0.245 R-free: 0.267

Authors:

J.A.Christopher,Z.Orgovan,M.Congreve,A.S.Dore,J.C.Errey,F.H.Marshall, J.S.Mason,K.Okrasa,P.Rucktooa,M.J.Serrano-Vega,G.G.Ferenczy, G.M.Keseru

Key ref:

J.A.Christopher et al. (2019). Structure-Based Optimization Strategies for G Protein-Coupled Receptor (GPCR) Allosteric Modulators: A Case Study from Analyses of New Metabotropic Glutamate Receptor 5 (mGlu₅) X-ray Structures. J Med Chem, 62, 207-222. PubMed id: 29455526 DOI: 10.1021/acs.jmedchem.7b01722

Date:

08-Jan-18 Release date: 07-Mar-18

Protein chain

P00720  (ENLYS_BPT4) -  Endolysin from Enterobacteria phage T4

Seq: 164 a.a.

Struc: 414 a.a.*

Protein chain

P41594  (GRM5_HUMAN) -  Metabotropic glutamate receptor 5 from Homo sapiens

Seq: 1212 a.a.

Struc: 414 a.a.*

* PDB and UniProt seqs differ at 173 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: 10.1021/acs.jmedchem.7b01722

J Med Chem 62:207-222 (2019)

PubMed id: 29455526

Structure-Based Optimization Strategies for G Protein-Coupled Receptor (GPCR) Allosteric Modulators: A Case Study from Analyses of New Metabotropic Glutamate Receptor 5 (mGlu₅) X-ray Structures.

J.A.Christopher, Z.Orgován, M.Congreve, A.S.Doré, J.C.Errey, F.H.Marshall, J.S.Mason, K.Okrasa, P.Rucktooa, M.J.Serrano-Vega, G.G.Ferenczy, G.M.Keserű.

ABSTRACT

Two interesting new X-ray structures of negative allosteric modulator (NAM) ligands for the mGlu₅ receptor, M-MPEP (3) and fenobam (4), are reported. The new structures show how the binding of the ligands induces different receptor water channel conformations to previously published structures. The structure of fenobam, where a urea replaces the acetylenic linker in M-MPEP and mavoglurant, reveals a binding mode where the ligand is rotated by 180° compared to a previously proposed docking model. The need for multiple ligand structures for accurate GPCR structure-based drug design is demonstrated by the different growing vectors identified for the head groups of M-MPEP and mavoglurant and by the unexpected water-mediated receptor interactions of a new chemotype represented by fenobam. The implications of the new structures for ligand design are discussed, with extensive analysis of the energetics of the water networks of both pseudoapo and bound structures providing a new design strategy for allosteric modulators.