PDBsum entry 6c7e

Hydrolase

PDB id: 6c7e

Contents

Protein chains

342 a.a.

Ligands

EOG ×4

Metals

_MG ×4

_ZN ×4

Waters ×1184

References listed in PDB file

Key reference

• Title: Mathematical and structural characterization of strong nonadditive structure-Activity relationship caused by protein conformational changes.
• Authors: L.Gomez, R.Xu, W.Sinko, B.Selfridge, W.Vernier, K.Ly, R.Truong, M.Metz, T.Marrone, K.Sebring, Y.Yan, B.Appleton, K.Aertgeerts, M.E.Massari, J.G.Breitenbucher.
• Ref.: J Med Chem, 2018, 61, 7754-7766. [DOI no: 10.1021/acs.jmedchem.8b00713]
• PubMed id: 30070482

Abstract

In medicinal chemistry, accurate prediction of additivity-based structure-activity relationship (SAR) analysis rests on three assumptions: (1) a consistent binding pose of the central scaffold, (2) no interaction between the R group substituents, and (3) a relatively rigid binding pocket in which the R group substituents act independently. Previously, examples of nonadditive SAR have been documented in systems that deviate from the first two assumptions. Local protein structural change upon ligand binding, through induced fit or conformational selection, although a well-known phenomenon that invalidates the third assumption, has not been linked to nonadditive SAR conclusively. Here, for the first time, we present clear structural evidence that the formation of a hydrophobic pocket upon ligand binding in PDE2 catalytic site reduces the size of another distinct subpocket and contributes to strong nonadditive SAR between two otherwise distant R groups.