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Protein & Peptide Letters
ISSN (Print): 0929-8665
ISSN (Online): 1875-5305
VOLUME: 21
ISSUE: 8
DOI: 10.2174/09298665113209990060      Price:  $58









Structure Function Analysis of Serpin Super-Family: "A Computational Approach"

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Author(s): Poonam Singh and Mohamad Aman Jairajpuri
Pages 714-721 (8)
Abstract:
Serine Protease inhibitors (serpins) are a super-family of proteins that controls the proteinases involved in the inflammation, complementation, coagulation and fibrinolytic pathways. Serpins are prone to conformational diseases due to a complex inhibition mechanism that involves large scale conformational change, and their susceptibility to undergo point mutations might lead to functional defects. Serpins are associated with diseases like emphysema/cirrhosis, angioedema, familial dementia, chronic obstructive bronchitis and thrombosis. Serpin polymerization based pathologies are fairly widespread and devising a cure has been difficult due to lack of clarity regarding its mechanism. Serpin can exist in various conformational states and has a variable cofactor binding ability. It has a large genome and proteome database which can be utilized to gain critical insight into their structure, mechanism and defects. Comprehensive computational studies on the serpin family is lacking, most of the work done till date is limited and deals mostly with few individual serpins. We have tried to analyze few aspect of this family using diverse computational biology tools and have shown the following: a) the importance of residue burial linked shift in the conformational stability as a major factor in increasing the polymer propensity in serpins. b) Amino acids involved in the polymerization are in general completely buried in the native conformation. c) An isozyme specific antithrombin study showed the structural basis of improved heparin binding to beta antithrombin as compared to alpha-antithrombin. d) A comprehensive cavity analysis showed its importance in inhibition and polymerizaiton and finally e) an interface analysis of various serpin protease complexes identified critical evolutionary conserved residues in exosite that determines its protease specificity. This work introduces the problem and emphasizes on the need for in-depth computational studies of serpin superfamily.
Keywords:
Antithrombin, molecular docking, protein cavities, protein polymerization, residue burial, serine protease inhibitors.
Affiliation:
Protein Conformation and Enzymology Lab, Department of Biosciences, Jamia Millia Islamia University, Jamia Nagar, New-Delhi 110025, India.