5JAH

Exploitation of a Novel Binding Pocket in Human Lipoprotein-Associated Phospholipase A2 (Lp-PLA₂) Discovered Through X-Ray Fragment Screening

Summary for 5JAH

• Entry DOI: 10.2210/pdb5jah/pdb
• Descriptor: Platelet-activating factor acetylhydrolase, CHLORIDE ION, 1,5,5-trimethylimidazolidine-2,4-dione, ... (4 entities in total)
• Functional Keywords: phospholipase, lipid metabolism, hydrolase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 44380.74

Authors

Day, P.J. (deposition date: 2016-04-12, release date: 2016-05-25, Last modification date: 2024-05-08)

Primary citation

Woolford, A.J.,Pero, J.E.,Aravapalli, S.,Berdini, V.,Coyle, J.E.,Day, P.J.,Dodson, A.M.,Grondin, P.,Holding, F.P.,Lee, L.Y.,Li, P.,Manas, E.S.,Marino, J.,Martin, A.C.,McCleland, B.W.,McMenamin, R.L.,Murray, C.W.,Neipp, C.E.,Page, L.W.,Patel, V.K.,Potvain, F.,Rich, S.,Rivero, R.A.,Smith, K.,Somers, D.O.,Trottet, L.,Velagaleti, R.,Williams, G.,Xie, R.
Exploitation of a Novel Binding Pocket in Human Lipoprotein-Associated Phospholipase A2 (Lp-PLA2) Discovered through X-ray Fragment Screening.
J.Med.Chem., 59:5356-5367, 2016

PubMed Abstract: Elevated levels of human lipoprotein-associated phospholipase A2 (Lp-PLA2) are associated with cardiovascular disease and dementia. A fragment screen was conducted against Lp-PLA2 in order to identify novel inhibitors. Multiple fragment hits were observed in different regions of the active site, including some hits that bound in a pocket created by movement of a protein side chain (approximately 13 Å from the catalytic residue Ser273). Using structure guided design, we optimized a fragment that bound in this pocket to generate a novel low nanomolar chemotype, which did not interact with the catalytic residues.

PubMed: 27167608
DOI: 10.1021/acs.jmedchem.6b00212

Experimental method

X-RAY DIFFRACTION (2.06 Å)