title: Crystal structure of calcium bound domain VI of calpain at 1.9 A resolution and its role in enzyme assembly, regulation, and inhibitor binding.
abstract: The three dimensional structure of calcium-bound domain VI of porcine calpain has been determined to 1.9 A 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 EF5'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 A resolution. A possible mode for calpain inhibition is discussed.
authors.affiliation: Center for Macromolecular Crystallography, University of Alabama at Birmingham 35294, USA.
authors.forename: G D
authors.initials: GD
authors.lastname: Lin
authors.forename: D
authors.initials: D
authors.lastname: Chattopadhyay
authors.forename: M
authors.initials: M
authors.lastname: Maki
authors.forename: K K
authors.initials: KK
authors.lastname: Wang
authors.forename: M
authors.initials: M
authors.lastname: Carson
authors.forename: L
authors.initials: L
authors.lastname: Jin
authors.forename: P W
authors.initials: PW
authors.lastname: Yuen
authors.forename: E
authors.initials: E
authors.lastname: Takano
authors.forename: M
authors.initials: M
authors.lastname: Hatanaka
authors.forename: L J
authors.initials: LJ
authors.lastname: DeLucas
authors.forename: S V
authors.initials: SV
authors.lastname: Narayana
mesh_terms: D000179:Acrylates / Q000737:chemistry / Q000378:metabolism*; D000595:Amino Acid Sequence; D001665:Binding Sites; D002118:Calcium / Q000378:metabolism*; D002154:Calpain / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism*; D018360:Crystallography, X-Ray; D015853:Cysteine Proteinase Inhibitors / Q000378:metabolism; D019281:Dimerization; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011487:Protein Conformation; D017510:Protein Folding; D017386:Sequence Homology, Amino Acid
chemical_list: D000179:Acrylates; D015853:Cysteine Proteinase Inhibitors; C100442:PD 150606; D002154:Calpain; D002118:Calcium