期刊
JOURNAL OF CHEMICAL INFORMATION AND MODELING
卷 51, 期 5, 页码 1074-1082出版社
AMER CHEMICAL SOC
DOI: 10.1021/ci200083f
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资金
- National Natural Science Foundation of China [20803048, 21073125, 20725312, 91021010]
- Chinese Ministry of Science and Technology [2007CB815201]
- National Institutes of Health [R03-AI071992]
Angiotensin-converting enzyme (ACE) is an important zinc-dependent hydrolase responsible for converting the inactive angiotensin I to the vasoconstrictor angiotensin II and for inactivating the vasodilator bradykinin. However, the substrate binding mode cif ACE has not been completely understood. In this work, we propose a model for an ACE Michaelis complex based on two known X-ray structures of inhibitor-enzyme complexes. Specifically, the human testis angiotensin-converting enzyme (tACE) complexed with two clinic drugs were first investigated using a combined quantum mechanical and molecular mechanical (QM/MM) approach. The structural parameters obtained from the 550 ps molecular dynamics simulations are in excellent agreement with the X-ray structures, validating the QM/MM approach. Based on these structures, a model for the Michaelis complex was proposed and simulated using the same computational protocol. Implications to ACE catalysis are discussed.
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