1TL9

High resolution crystal structure of calpain I protease core in complex with leupeptin

Summary for 1TL9

• Entry DOI: 10.2210/pdb1tl9/pdb
• Related: 1DFO 1KFU 1KFX 1KXR 1MDW 1NX0 1TLO
• Related PRD ID: PRD_000216
• Descriptor: Calpain 1, large [catalytic] subunit, leupeptin inhibitor, CALCIUM ION, ... (4 entities in total)
• Functional Keywords: covalently-linked inhibitor at the active site cysteine forms a hemithioacetal, hydrolase, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Rattus norvegicus (Norway rat); More
• Cellular location: Cytoplasm (By similarity): P97571
• Total number of polymer chains: 2
• Total formula weight: 39314.29

Authors

Moldoveanu, T.,Campbell, R.L.,Cuerrier, D.,Davies, P.L. (deposition date: 2004-06-09, release date: 2004-11-02, Last modification date: 2024-11-20)

Primary citation

Moldoveanu, T.,Campbell, R.L.,Cuerrier, D.,Davies, P.L.
Crystal Structures of Calpain-E64 and -Leupeptin Inhibitor Complexes Reveal Mobile Loops Gating the Active Site
J.Mol.Biol., 343:1313-1326, 2004

PubMed Abstract: The endogenous calpain inhibitor, calpastatin, modulates some patho-physiological aspects of calpain signaling. Excess calpain can escape this inhibition and as well, many calpain isoforms and autolytically generated protease core fragments are not inhibited by calpastatin. There is a need, therefore, to develop specific, cell-permeable calpain inhibitors to block uncontrolled proteolysis and prevent tissue damage during brain and heart ischemia, spinal-cord injury and Alzheimer's diseases. Here, we report the first high-resolution crystal structures of rat mu-calpain protease core complexed with two traditional, low molecular mass inhibitors, leupeptin and E64. These structures show that access to a slightly deeper, but otherwise papain-like active site is gated by two flexible loops. These loops are divergent among the calpain isoforms giving a potential structural basis for substrate/inhibitor selectivity over other papain-like cysteine proteases and between members of the calpain family.

PubMed: 15491615
DOI: 10.1016/j.jmb.2004.09.016

Experimental method

X-RAY DIFFRACTION (1.8 Å)