Exploring conformation changes of Janus kinase 2 pseudokinase mediated by mutations through Gaussian accelerated molecular dynamics and principal component analysis
被引:12
作者:
Bao, Huayin
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机构:
Shandong Univ Tradit Chinese Med, Sch Pharm, Jinan, Peoples R ChinaShandong Univ Tradit Chinese Med, Sch Pharm, Jinan, Peoples R China
Bao, Huayin
[1
]
He, Weikai
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机构:
Shandong Jiaotong Univ, Sch Sci, Jinan, Peoples R ChinaShandong Univ Tradit Chinese Med, Sch Pharm, Jinan, Peoples R China
He, Weikai
[2
]
Chen, Jianzhong
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机构:
Shandong Jiaotong Univ, Sch Sci, Jinan, Peoples R ChinaShandong Univ Tradit Chinese Med, Sch Pharm, Jinan, Peoples R China
Chen, Jianzhong
[2
]
机构:
[1] Shandong Univ Tradit Chinese Med, Sch Pharm, Jinan, Peoples R China
[2] Shandong Jiaotong Univ, Sch Sci, Jinan, Peoples R China
Protein tyrosine kinase;
pseudokinase domain;
GaMD simulations;
free energy landscape;
principal component analysis;
JAK2 TYROSINE KINASE;
FREE-ENERGY;
PROTEIN-KINASE;
MECHANISM;
DOMAIN;
BINDING;
ACTIVATION;
AMBER;
SIMULATIONS;
IDENTIFICATION;
D O I:
10.1080/07391102.2023.2260486
中图分类号:
Q5 [生物化学];
Q7 [分子生物学];
学科分类号:
071010 ;
081704 ;
摘要:
The pseudokinase domain (JH2) of the protein tyrosine kinase (Janus kinase 2, JAK2) regulates the activity of a tyrosine kinase domain (JH1) in JAK2, which is further affected by mutations in the JH2. In this work, Gaussian accelerated molecular dynamics (GaMD) simulations followed by construction of free energy landscapes (FELs) and principal component analysis (PCA) were performed to study effect of two mutations V617F and V617F/E596A on the conformations of the ATP-bound JH2. The dynamic analyses reveal that mutations affect the structural flexibility and correlated motions of the JH2, meanwhile also change the dynamics behavior of the P-loop and & alpha;C-helix of the JH2. The information from FELs unveils that mutations induce less energy states than the free JH2 and the WT one. The analyses of interaction networks uncover that mutations affect the salt bridge interactions of ATP with K581, K677 and R715 and alter hydrogen bonding interactions (HBIs) of ATP with the JH2. The changes in conformations of the JH2 and ATP-JH2 interaction networks caused by mutations in turn generate effect on the activity regulations of the JH2 on the JH1. This work is expected to provide significant theoretical helps for deeply understanding the function of the JH2 and drug design toward JAK2.Communicated by Ramaswamy H. Sarma
机构:
NYU, Sch Med, Struct Biol Program, Kimmel Ctr Biol & Med,Skirball Inst, New York, NY 10012 USA
NYU, Sch Med, Dept Biochem & Mol Pharmacol, New York, NY USANYU, Sch Med, Struct Biol Program, Kimmel Ctr Biol & Med,Skirball Inst, New York, NY 10012 USA
Bandaranayake, Rajintha M.
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Ungureanu, Daniela
Shan, Yibing
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机构:
DE Shaw Res, New York, NY USANYU, Sch Med, Struct Biol Program, Kimmel Ctr Biol & Med,Skirball Inst, New York, NY 10012 USA
Shan, Yibing
Shaw, David E.
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机构:
DE Shaw Res, New York, NY USA
Columbia Univ, Ctr Computat Biol & Bioinformat, New York, NY USANYU, Sch Med, Struct Biol Program, Kimmel Ctr Biol & Med,Skirball Inst, New York, NY 10012 USA
Shaw, David E.
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Silvennoinen, Olli
Hubbard, Stevan R.
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机构:
NYU, Sch Med, Struct Biol Program, Kimmel Ctr Biol & Med,Skirball Inst, New York, NY 10012 USA
NYU, Sch Med, Dept Biochem & Mol Pharmacol, New York, NY USANYU, Sch Med, Struct Biol Program, Kimmel Ctr Biol & Med,Skirball Inst, New York, NY 10012 USA
机构:
NYU, Sch Med, Struct Biol Program, Kimmel Ctr Biol & Med,Skirball Inst, New York, NY 10012 USA
NYU, Sch Med, Dept Biochem & Mol Pharmacol, New York, NY USANYU, Sch Med, Struct Biol Program, Kimmel Ctr Biol & Med,Skirball Inst, New York, NY 10012 USA
Bandaranayake, Rajintha M.
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Ungureanu, Daniela
Shan, Yibing
论文数: 0引用数: 0
h-index: 0
机构:
DE Shaw Res, New York, NY USANYU, Sch Med, Struct Biol Program, Kimmel Ctr Biol & Med,Skirball Inst, New York, NY 10012 USA
Shan, Yibing
Shaw, David E.
论文数: 0引用数: 0
h-index: 0
机构:
DE Shaw Res, New York, NY USA
Columbia Univ, Ctr Computat Biol & Bioinformat, New York, NY USANYU, Sch Med, Struct Biol Program, Kimmel Ctr Biol & Med,Skirball Inst, New York, NY 10012 USA
Shaw, David E.
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h-index:
机构:
Silvennoinen, Olli
Hubbard, Stevan R.
论文数: 0引用数: 0
h-index: 0
机构:
NYU, Sch Med, Struct Biol Program, Kimmel Ctr Biol & Med,Skirball Inst, New York, NY 10012 USA
NYU, Sch Med, Dept Biochem & Mol Pharmacol, New York, NY USANYU, Sch Med, Struct Biol Program, Kimmel Ctr Biol & Med,Skirball Inst, New York, NY 10012 USA