期刊
JOURNAL OF PHYSICAL CHEMISTRY B
卷 120, 期 46, 页码 11873-11879出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.jpcb.6b07827
关键词
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资金
- Core Research for Evolutional Science and Technology (CREST) Establishment of Molecular Technology towards the Creation of New Functions of the Japan Science Technology Agency (JST)
- Ministry of Education, Culture, Sport, Science and Technology (MEXT) in Japan
- MEXT
Thrombin is a serine protease involved in the blood coagulation reaction, and it shows maximum enzymatic activity in the presence of Na+ It has been supposed that Na+ binding promotes conversion from the inactive form, with a collapsed primary substrate pocket (S1 pocket), to the active form, with a properly formed S1 pocket. However, the evidence supporting this activation mechanism was derived from the X-ray crystallographic structures solved under nonphysiological conditions and using thrombin mutants; thus, it still remains elusive whether the activation mechanism is actually attributed to Na+ binding. To address the problem, we employed all-atom molecular dynamics simulations for both active and inactive forms of thrombin in the presence and absence of Na+ binding and examined the effect of Na+ binding on S1-pocket formation. In contrast to the conventional supposition, we revealed that Na+ binding does not prevent S1-pocket collapse virtually, but rather, the bound Na+ can move to the S1 pocket, thus blocking substrate access directly. Additionally, it was clarified that Na+ binding does not promote S1-pocket formation. According to these insights, we concluded that Na+ binding is irrelevant to the interconversion between the inactive and active forms of thrombin.
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