6C7D

Crystal structure of human phosphodiesterase 2A with N-(1-adamantyl)-1-(2-chlorophenyl)-4-methyl-[1,2,4]triazolo[4,3-a]quinoxaline-8-carboxamide

6C7D の概要

• エントリーDOI: 10.2210/pdb6c7d/pdb
• 分子名称: cGMP-dependent 3',5'-cyclic phosphodiesterase, 1-(2-chlorophenyl)-4-methyl-N-[(3s,5s,7s)-tricyclo[3.3.1.1~3,7~]decan-1-yl][1,2,4]triazolo[4,3-a]quinoxaline-8-carboxamide, ZINC ION, ... (5 entities in total)
• 機能のキーワード: phosphodiesterase, hydrolase
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 161886.08

構造登録者

Xu, R.,Aertgeerts, K. (登録日: 2018-01-22, 公開日: 2018-08-15, 最終更新日: 2024-03-13)

主引用文献

Gomez, L.,Xu, R.,Sinko, W.,Selfridge, B.,Vernier, W.,Ly, K.,Truong, R.,Metz, M.,Marrone, T.,Sebring, K.,Yan, Y.,Appleton, B.,Aertgeerts, K.,Massari, M.E.,Breitenbucher, J.G.
Mathematical and Structural Characterization of Strong Nonadditive Structure-Activity Relationship Caused by Protein Conformational Changes.
J. Med. Chem., 61:7754-7766, 2018

PubMed 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.

PubMed: 30070482
DOI: 10.1021/acs.jmedchem.8b00713

実験手法

X-RAY DIFFRACTION (1.79 Å)