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Crystal structure of calcium bound domain VI of calpain at 1.9 Å resolution and its role in enzyme assembly, regulation, and inhibitor binding

Nature Structural Biology volume 4, pages 539–547 (1997)Cite this article

Abstract

The three dimensional structure of calcium-bound domain VI of porcine calpain has been determined to 1.9 Å resolution. The crystal structure reveals five EF-hands, one more than previously suggested. There are two EF-hand pairs, one pair (EF1-EF2) displays an ‘open’ conformation and the other (EF3-EF4) a ‘closed’ conformation. Unusually, a calcium atom is found at the C-terminal end of the calcium binding loop of EF4. With two additional residues in the calcium binding loop, the fifth EF-hand (EF5) is in a ‘closed’ conformation. EF5 pairs up with the corresponding fifth EF-hand of a non-crystallographically related molecule. Considering the EFS's role in a homodimer formation of domain VI, we suggest a model for the assembly of heterodimeric calpain. The crystal structure of a Ca2+ bound domain VI–inhibitor (PD150606) complex has been refined to 2.1 Å resolution. A possible mode for calpain inhibition is discussed.

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Authors and Affiliations

  1. Center for Macromolecular Crystallography, University of Alabama at Birmingham, Birmingham, Alabama, 35294, USA

    Guang-da Lin, Debasish Chattopadhyay, Mike Carson, Lei Jin, Lawrence J. DeLucas & Sthanam V.L. Narayana

  2. School of Agriculture, Nagoya University, Nagoya, Japan

    Masatoshi Maki

  3. Neuroscience Therapeutics, Parke-Davis Pharmaceutical Research, Warner Lambert Company, USA

    Kevin K. W. Wang

  4. Institute for Virus Research, Kyoto University, Kyoto, Japan

    Emiko Takano & Masakazu Hatanaka

  5. Medicinal Chemistry, Parke-Davis Pharmaceutical Research, Warner Lambert Company, USA

    Po-wai Yuen

  6. School of Optometry, University of Alabama at Birmingham, USA

    Lawrence J. DeLucas & Sthanam V.L. Narayana

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  1. Guang-da Lin
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Correspondence to Sthanam V.L. Narayana.

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Lin, Gd., Chattopadhyay, D., Maki, M. et al. Crystal structure of calcium bound domain VI of calpain at 1.9 Å resolution and its role in enzyme assembly, regulation, and inhibitor binding. Nat Struct Mol Biol 4, 539–547 (1997). https://doi.org/10.1038/nsb0797-539

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