4YL1

Crystal Structures of mPGES-1 Inhibitor Complexes

Summary for 4YL1

• Entry DOI: 10.2210/pdb4yl1/pdb
• Related: 4YK5 4YL0 4YL3
• Descriptor: Prostaglandin E synthase, 5-(4-tert-butylphenyl)-1-[4-(propan-2-yloxy)phenyl]-1H-indole-2-carboxylic acid, DI(HYDROXYETHYL)ETHER, ... (7 entities in total)
• Functional Keywords: inhibitor, inflammation, prostaglandin, isomerase-isomerase inhibitor complex, isomerase/isomerase inhibitor
• Biological source: Homo sapiens (Human)
• Cellular location: Membrane ; Multi-pass membrane protein : O14684
• Total number of polymer chains: 1
• Total formula weight: 18305.73

Authors

Luz, J.G.,Antonysamy, S.,Kuklish, S.L.,Fisher, M.J. (deposition date: 2015-03-04, release date: 2015-06-10, Last modification date: 2024-02-28)

Primary citation

Luz, J.G.,Antonysamy, S.,Kuklish, S.L.,Condon, B.,Lee, M.R.,Allison, D.,Yu, X.P.,Chandrasekhar, S.,Backer, R.,Zhang, A.,Russell, M.,Chang, S.S.,Harvey, A.,Sloan, A.V.,Fisher, M.J.
Crystal Structures of mPGES-1 Inhibitor Complexes Form a Basis for the Rational Design of Potent Analgesic and Anti-Inflammatory Therapeutics.
J.Med.Chem., 58:4727-4737, 2015

PubMed Abstract: Microsomal prostaglandin E synthase 1 (mPGES-1) is an α-helical homotrimeric integral membrane inducible enzyme that catalyzes the formation of prostaglandin E2 (PGE2) from prostaglandin H2 (PGH2). Inhibition of mPGES-1 has been proposed as a therapeutic strategy for the treatment of pain, inflammation, and some cancers. Interest in mPGES-1 inhibition can, in part, be attributed to the potential circumvention of cardiovascular risks associated with anti-inflammatory cyclooxygenase 2 inhibitors (coxibs) by targeting the prostaglandin pathway downstream of PGH2 synthesis and avoiding suppression of antithrombotic prostacyclin production. We determined the crystal structure of mPGES-1 bound to four potent inhibitors in order to understand their structure-activity relationships and provide a framework for the rational design of improved molecules. In addition, we developed a light-scattering-based thermal stability assay to identify molecules for crystallographic studies.

PubMed: 25961169
DOI: 10.1021/acs.jmedchem.5b00330

Experimental method

X-RAY DIFFRACTION (1.41 Å)