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Int. J. Mol. Sci. 2014, 15(5), 7897-7938;

Homology Modeling Study of Bovine μ-Calpain Inhibitor-Binding Domains

Animal Genome & Bioinformatics Division, National Institute of Animal Science, RDA, Suwon 441-706, Korea
Hanwoo Experiment Station, National Institute of Animal Science, RDA, PyeongChang 232-950, Korea
Division of Biosafety Evaluation and Control, Korea National Institute of Helth 187 Osongsaengmyeong2-ro, Gango-myeon, Cheongwon-gun, Chungcheongbuk-do 363-951, Korea
Insilicotech Co., Ltd., C-602 Korea Bio Park, 694-1 Sampyeong-Dong, Bundang-Gu, Seongnam-Shi, Gyeonggi-do 463-400, Korea
Author to whom correspondence should be addressed.
Received: 12 February 2014 / Revised: 15 April 2014 / Accepted: 16 April 2014 / Published: 6 May 2014
(This article belongs to the Section Physical Chemistry, Theoretical and Computational Chemistry)
Full-Text   |   PDF [4994 KB, uploaded 19 June 2014]


The activated mammalian CAPN-structures, the CAPN/CAST complex in particular, have become an invaluable target model using the structure-based virtual screening of drug candidates from the discovery phase to development for over-activated CAPN linked to several diseases, such as post-ischemic injury and cataract formation. The effect of Ca2+-binding to the enzyme is thought to include activation, as well as the dissociation, aggregation, and autolysis of small regular subunits. Unfortunately, the Ca2+-activated enzyme tends to aggregate when provided as a divalent ion at the high-concentration required for the protease crystallization. This is also makes it very difficult to crystallize the whole-length enzyme itself, as well as the enzyme-inhibitor complex. Several parameters that influence CAPN activity have been investigated to determine its roles in Ca2+-modulation, autoproteolysis, phosphorylation, and intracellular distribution and inhibition by its endogenous inhibitor CAST. CAST binds and inhibits CAPN via its CAPN-inhibitor domains (four repeating domains 1–4; CAST1–4) when CAPN is activated by Ca2+-binding. An important key to understanding CAPN1 inhibition by CAST is to determine how CAST interacts at the molecular level with CAPN1 to inhibit its protease activity. In this study, a 3D structure model of a CAPN1 bound bovine CAST4 complex was built by comparative modeling based on the only known template structure of a rat CAPN2/CAST4 complex. The complex model suggests certain residues of bovine CAST4, notably, the TIPPKYQ motif sequence, and the structural elements of these residues, which are important for CAPN1 inhibition. In particular, as CAST4 docks near the flexible active site of CAPN1, conformational changes at the interaction site after binding could be directly related to CAST4 inhibitory activity. These functional interfaces can serve as a guide to the site-mutagenesis in research on bovine CAPN1 structure-function relationships for the design of small molecules inhibitors to prevent uncontrolled and unspecific degradation in the proteolysis of key protease substrates. View Full-Text
Keywords: CAPN (Calpain); CAST4 (Calpain 4 domain); homology modeling; protease regulation system CAPN (Calpain); CAST4 (Calpain 4 domain); homology modeling; protease regulation system
This is an open access article distributed under the Creative Commons Attribution License (CC BY 3.0).

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Chai, H.-H.; Lim, D.; Lee, S.-H.; Chai, H.-Y.; Jung, E. Homology Modeling Study of Bovine μ-Calpain Inhibitor-Binding Domains. Int. J. Mol. Sci. 2014, 15, 7897-7938.

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