5CGC

Structure of the human class C GPCR metabotropic glutamate receptor 5 transmembrane domain in complex with the negative allosteric modulator 3-chloro-4-fluoro-5-[6-(1H-pyrazol-1-yl)pyrimidin-4-yl]benzonitrile

Summary for 5CGC

• Entry DOI: 10.2210/pdb5cgc/pdb
• Related: 4OO9
• Descriptor: Metabotropic glutamate receptor 5,Endolysin,Metabotropic glutamate receptor 5, OLEIC ACID, 2-(N-MORPHOLINO)-ETHANESULFONIC ACID, ... (5 entities in total)
• Functional Keywords: 7tm, receptor, gpcr, membrane-protein, signaling protein
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 1
• Total formula weight: 51427.30

Authors

Christopher, J.A.,Aves, S.J.,Bennett, K.A.,Dore, A.S.,Errey, J.C.,Jazayeri, A.,Marshall, F.H.,Okrasa, K.,Serrano-Vega, M.J.,Tehan, B.G.,Wiggin, G.R.,Congreve, M. (deposition date: 2015-07-09, release date: 2015-08-12, Last modification date: 2024-11-20)

Primary citation

Christopher, J.A.,Aves, S.J.,Bennett, K.A.,Dore, A.S.,Errey, J.C.,Jazayeri, A.,Marshall, F.H.,Okrasa, K.,Serrano-Vega, M.J.,Tehan, B.G.,Wiggin, G.R.,Congreve, M.
Fragment and Structure-Based Drug Discovery for a Class C GPCR: Discovery of the mGlu5 Negative Allosteric Modulator HTL14242 (3-Chloro-5-[6-(5-fluoropyridin-2-yl)pyrimidin-4-yl]benzonitrile).
J.Med.Chem., 58:6653-6664, 2015

PubMed Abstract: Fragment screening of a thermostabilized mGlu5 receptor using a high-concentration radioligand binding assay enabled the identification of moderate affinity, high ligand efficiency (LE) pyrimidine hit 5. Subsequent optimization using structure-based drug discovery methods led to the selection of 25, HTL14242, as an advanced lead compound for further development. Structures of the stabilized mGlu5 receptor complexed with 25 and another molecule in the series, 14, were determined at resolutions of 2.6 and 3.1 Å, respectively.

PubMed: 26225459
DOI: 10.1021/acs.jmedchem.5b00892

Experimental method

X-RAY DIFFRACTION (3.101 Å)