2G63

Crystal structure of human dipeptidyl peptidase IV (DPPIV) complexed with cyanopyrrolidine (C5-pro-pro) inhibitor 24b

2G63 の概要

• エントリーDOI: 10.2210/pdb2g63/pdb
• 関連するPDBエントリー: 2G5P 2G5T
• 分子名称: Dipeptidyl peptidase 4, METHYL 4-{[({[(2R,5S)-5-{[(2S)-2-(AMINOMETHYL)PYRROLIDIN-1-YL]CARBONYL}PYRROLIDIN-2-YL]METHYL}AMINO)CARBONYL]AMINO}BENZOATE (3 entities in total)
• 機能のキーワード: serine peptidase, beta-propeller, hydrolase
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Dipeptidyl peptidase 4 soluble form: Secreted . Cell membrane ; Single- pass type II membrane protein: P27487
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 337412.82

構造登録者

Longenecker, K.L.,Fry, E.H.,Lake, M.R.,Solomon, L.R.,Pei, Z.,Li, X. (登録日: 2006-02-24, 公開日: 2006-07-04, 最終更新日: 2024-10-30)

主引用文献

Pei, Z.,Li, X.,Longenecker, K.,Von Geldern, T.W.,Wiedeman, P.E.,Lubben, T.H.,Zinker, B.A.,Stewart, K.,Ballaron, S.J.,Stashko, M.A.,Mika, A.K.,Beno, D.W.,Long, M.,Wells, H.,Kempf-Grote, A.J.,Madar, D.J.,McDermott, T.S.,Bhagavatula, L.,Fickes, M.G.,Pireh, D.,Solomon, L.R.,Lake, M.R.,Edalji, R.,Fry, E.H.,Sham, H.L.,Trevillyan, J.M.
Discovery, structure-activity relationship, and pharmacological evaluation of (5-substituted-pyrrolidinyl-2-carbonyl)-2-cyanopyrrolidines as potent dipeptidyl peptidase IV inhibitors.
J.Med.Chem., 49:3520-3535, 2006

PubMed Abstract: A series of (5-substituted pyrrolidinyl-2-carbonyl)-2-cyanopyrrolidine (C5-Pro-Pro) analogues was discovered as dipeptidyl peptidase IV (DPPIV) inhibitors as a potential treatment of diabetes and obesity. X-ray crystallography data show that these inhibitors bind to the catalytic site of DPPIV with the cyano group forming a covalent bond with the serine residue of DPPIV. The C5-substituents make various interactions with the enzyme and affect potency, chemical stability, selectivity, and PK properties of the inhibitors. Optimized analogues are extremely potent with subnanomolar K(i)'s, are chemically stable, show very little potency decrease in the presence of plasma, and exhibit more than 1,000-fold selectivity against related peptidases. The best compounds also possess good PK and are efficacious in lowering blood glucose in an oral glucose tolerance test in ZDF rats.

PubMed: 16759095
DOI: 10.1021/jm051283e

実験手法

X-RAY DIFFRACTION (2 Å)