5JAR

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

5JAR の概要

• エントリーDOI: 10.2210/pdb5jar/pdb
• 分子名称: Platelet-activating factor acetylhydrolase, DIMETHYL SULFOXIDE, CHLORIDE ION, ... (5 entities in total)
• 機能のキーワード: phospholipase, lipid metabolism, hydrolase
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 44645.55

構造登録者

Day, P.J. (登録日: 2016-04-12, 公開日: 2016-05-25, 最終更新日: 2024-05-08)

主引用文献

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

実験手法

X-RAY DIFFRACTION (2.11 Å)