2g8e
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Calpain 1 proteolytic core in complex with SNJ-1715, a cyclic hemiacetal-type inhibitor
OverviewOverview
Calpains are intracellular calcium-activated cysteine proteases whose, unregulated proteolysis following the loss of calcium homeostasis can lead, to acute degeneration during ischemic episodes and trauma, as well as, Alzheimer's disease and cataract formation. The determination of the, crystal structure of the proteolytic core of mu-calpain (muI-II) in a, calcium-bound active conformation has made structure-guided design of, active site inhibitors feasible. We present here high-resolution crystal, structures of rat muI-II complexed with two reversible calpain-specific, inhibitors employing cyclic hemiacetal (SNJ-1715) and alpha-ketoamide, (SNJ-1945) chemistries that reveal new details about the interactions of, inhibitors with this enzyme. The SNJ-1715 complex confirms that the free, aldehyde is the reactive species of the cornea-permeable cyclic, hemiacetal. The alpha-ketoamide warhead of SNJ-1945 binds with the, hydroxyl group of the tetrahedral adduct pointing toward the catalytic, histidine rather than the oxyanion hole. The muI-II-SNJ-1945 complex shows, residue Glu261 displaced from the S1' site by the inhibitor, resulting in, an extended "open" conformation of the domain II gating loop and an, unobstructed S1' site. This conformation offers an additional template for, structure-based drug design extending to the primed subsites. An important, role for the highly conserved Glu261 is proposed.
About this StructureAbout this Structure
2G8E is a Single protein structure of sequence from Rattus norvegicus with CA, D5G and MES as ligands. Active as Calpain-1, with EC number 3.4.22.52 Full crystallographic information is available from OCA.
ReferenceReference
Calpain inhibition by alpha-ketoamide and cyclic hemiacetal inhibitors revealed by X-ray crystallography., Cuerrier D, Moldoveanu T, Inoue J, Davies PL, Campbell RL, Biochemistry. 2006 Jun 20;45(24):7446-52. PMID:16768440
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