1ITO

Crystal Structure Analysis of Bovine Spleen Cathepsin B-E64c complex

Summary for 1ITO

• Entry DOI: 10.2210/pdb1ito/pdb
• Related: 1DQD
• Descriptor: Cathepsin B, N-[1-HYDROXYCARBOXYETHYL-CARBONYL]LEUCYLAMINO-2-METHYL-BUTANE (3 entities in total)
• Functional Keywords: cathepsin b, cysteine protease, e64c, hydrolase
• Biological source: Bos taurus (cattle)
• Cellular location: Lysosome : P07688
• Total number of polymer chains: 1
• Total formula weight: 28235.43

Authors

Yamamoto, A.,Tomoo, T.,Matsugi, K.,Hara, T.,In, Y.,Murata, M.,Kitamura, K.,Ishida, T. (deposition date: 2002-01-19, release date: 2003-01-19, Last modification date: 2023-10-25)

Primary citation

Yamamoto, A.,Tomoo, T.,Matsugi, K.,Hara, T.,In, Y.,Murata, M.,Kitamura, K.,Ishida, T.
Structural basis for development of cathepsin B-specific noncovalent-type inhibitor: crystal structure of cathepsin B-E64c complex
BIOCHIM.BIOPHYS.ACTA, 1597:244-251, 2002

PubMed Abstract: In order to elucidate the substrate specificity of the Sn subsites (n=1-3) of cathepsin B, its crystal structure inhibited by E64c [(+)-(2S,3S)-3-(1-[N-(3-methylbutyl)amino]-leucylcarbonyl)oxirane-2-carboxylic acid] was analyzed by the X-ray diffraction method. Iterative manual rebuilding and convenient conjugate refinement of structure decreased R- and free R-factors to 19.7% and to 23.9%, respectively, where 130 water molecules were included for the refinement using 14,759 independent reflections from 10 to 2.3 A resolution. The epoxy carbonyl carbon of E64c was covalently bonded to the Cys(29) S(gamma) atom and the remaining parts were located at Sn subsites (n=1-3). The substrate specificity of these subsites was characterized based on their interactions with the inhibitor. Base on these structural data, we developed a novel cathepsin B-specific noncovalent-type inhibitor, which may bind to S2'-S3. The molecular design of possessing structural elements of both CA074 and E64c, assisted by energy minimization and molecular dynamics (MD) simulation, may lead to a new lead noncovalent-type inhibitor.

PubMed: 12044902
DOI: 10.1016/S0167-4838(02)00284-4

Experimental method

X-RAY DIFFRACTION (2.286 Å)