Document Detail

Molecular dynamics simulation of PNPLA3 I148M polymorphism reveals reduced substrate access to the catalytic cavity.
MedLine Citation:
PMID:  23042597     Owner:  NLM     Status:  Publisher    
A missense mutation I148M in PNPLA3 (patatin-like phospholipase domain-containing 3 protein) is significantly correlated with nonalcoholic fatty liver disease. To glean insights into mutation's effect on enzymatic activity, we performed molecular dynamics simulation and flexible docking studies. Our data shows that the size of the substrate-access entry site is significantly reduced in mutants, which limits the access of palmitic acid to the catalytic dyad. Besides, the binding free energy calculations suggest low-affinity for substrate to mutant enzyme. The substrate-bound system simulations reveal that the spatial arrangement of palmitic acid is distinct in wild-type from that in mutant. The substrate recognition specificity is lost due to the loop where the I148M mutation was located. Our results provide strong evidence for the mechanism by which I148M affects the enzyme activity and suggest that mediating the dynamics may offer a potential avenue for NAFLD. Proteins 2012. © 2012 Wiley Periodicals, Inc.
Yong-Ning Xin; Yuqi Zhao; Zhong-Hua Lin; Xiangjun Jiang; Shi-Ying Xuan; Jingfei Huang
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2012-10-8
Journal Detail:
Title:  Proteins     Volume:  -     ISSN:  1097-0134     ISO Abbreviation:  Proteins     Publication Date:  2012 Oct 
Date Detail:
Created Date:  2012-10-8     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  8700181     Medline TA:  Proteins     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Copyright Information:
Copyright © 2012 Wiley Periodicals, Inc.
College of Medicine and Pharmaceutics, Ocean University of China, Qingdao 266003, Shandong Province, China; Qingdao Municipal Hospital, Qingdao 266021, Shandong Province, China.
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