2IL2

Crystal Structure of Human Renin Complexed with Inhibitor

2IL2 の概要

• エントリーDOI: 10.2210/pdb2il2/pdb
• 関連するPDBエントリー: 2IKO 2IKU
• 分子名称: Renin, N-[2-({2-AMINO-6-ETHYL-5-[4-(3-METHOXYPROPYL)-2,2-DIMETHYL-3-OXO-3,4-DIHYDRO-2H-1,4-BENZOXAZIN-6-YL]PYRIMIDIN-4-YL}AMINO)ETHYL]NAPHTHALENE-2-SULFONAMIDE, CITRIC ACID, ... (4 entities in total)
• 機能のキーワード: renin, inhibitors, drug design, hydrolase
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Secreted: P00797
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 75963.63

構造登録者

Mochalkin, I. (登録日: 2006-10-02, 公開日: 2006-12-05, 最終更新日: 2024-10-09)

主引用文献

Sarver, R.W.,Peevers, J.,Cody, W.L.,Ciske, F.L.,Dyer, J.,Emerson, S.D.,Hagadorn, J.C.,Holsworth, D.D.,Jalaie, M.,Kaufman, M.,Mastronardi, M.,McConnell, P.,Powell, N.A.,Quin, J.,Van Huis, C.A.,Zhang, E.,Mochalkin, I.
Binding thermodynamics of substituted diaminopyrimidine renin inhibitors.
Anal.Biochem., 360:30-40, 2007

PubMed Abstract: Renin is an aspartyl protease involved in the production of angiotensin II, a potent vasoconstrictor. Renin inhibitors can prevent blood vessel constriction and therefore could be useful for the treatment of hypertension. High-throughput screening efforts identified a small molecule renin inhibitor with a core substituted diaminopyrimidine ring. Parallel medicinal chemistry efforts based on this lead resulted in compound 1. A complex of 1 bound to renin was crystallized, and structural data were obtained by X-ray diffraction. The structure indicated that there were adjacent unoccupied binding pockets. Synthetic efforts were initiated to extend functionality into these pockets so as to improve affinity and adjust pharmacokinetic parameters. Thermodynamics data for inhibitor binding to renin were also collected using isothermal titration calorimetry. These data were used to help guide inhibitor optimization by suggesting molecular alterations to improve binding affinity from both thermodynamic and structural perspectives. The addition of a methoxypropyl group extending into the S3 subpocket improved inhibitor affinity and resulted in greater binding enthalpy. Initial additions to the pyrimidine ring template that extended into the large hydrophobic S2 pocket did not improve affinity and dramatically altered the thermodynamic driving force for the binding interaction. Binding of the core template was enthalpically driven, whereas binding of initial inhibitors with S2 extensions was both enthalpically and entropically driven but lost significant binding enthalpy. Additional electrostatic interactions were then incorporated into the S2 extension to improve binding enthalpy while taking advantage of the favorable entropy.

PubMed: 17113558
DOI: 10.1016/j.ab.2006.10.017

実験手法

X-RAY DIFFRACTION (2.24 Å)