1DCY

CRYSTAL STRUCTURE OF HUMAN S-PLA2 IN COMPLEX WITH INDOLE 3 ACTIVE SITE INHIBITOR

Summary for 1DCY

• Entry DOI: 10.2210/pdb1dcy/pdb
• Related: 1DB4 1DB5
• Descriptor: PHOSPHOLIPASE A2, CALCIUM ION, 1-BENZYL-5-METHOXY-2-METHYL-1H-INDOL-3-YL)-ACETIC ACID, ... (4 entities in total)
• Functional Keywords: s-pla2; structure-based drug design, hydrolase/hydrolase inhibitor, hydrolase-hydrolase inhibitor complex
• Biological source: Homo sapiens (human)
• Cellular location: Membrane; Peripheral membrane protein: P14555
• Total number of polymer chains: 1
• Total formula weight: 14334.53

Authors

Chirgadze, N.Y.,Schevitz, R.W.,Wery, J.-P. (deposition date: 1999-11-05, release date: 1999-11-12, Last modification date: 2024-10-30)

Primary citation

Schevitz, R.W.,Bach, N.J.,Carlson, D.G.,Chirgadze, N.Y.,Clawson, D.K.,D Dillard, R.,Draheim, S.D.,Hartley, L.W.,Jones, N.D.,Mihelich, E.D.,L Olkowski, J.,Snyder, D.W.,Dand, S.C.,Wery, J.-P.
Structure-based design of the first potent and selective inhibitor of human non-pancreatic secretory phospholipase A2.
Nat.Struct.Biol., 2:458-465, 1995

PubMed Abstract: A lead compound obtained from a high volume human non-pancreatic secretory phospholipase A2 (hnps-PLA2) screen has been developed into a potent inhibitor using detailed structural knowledge of inhibitor binding to the enzyme active site. Four crystal structures of hnps-PLA2 complexed with a series of increasingly potent indole inhibitors were determined and used as the structural basis for both understanding this binding and providing valuable insights for further development. The application of structure-based drug design has made possible improvements in the binding of this screening lead to the enzyme by nearly three orders of magnitude. Furthermore, the optimized structure (LY311727) displayed 1,500-fold selectivity when assayed against porcine pancreatic s-PLA2.

PubMed: 7664108
DOI: 10.1038/nsb0695-458

Experimental method

X-RAY DIFFRACTION (2.7 Å)