2g8e

Calpain 1 proteolytic core in complex with SNJ-1715, a cyclic hemiacetal-type inhibitorCalpain 1 proteolytic core in complex with SNJ-1715, a cyclic hemiacetal-type inhibitor

Structural highlights 2g8e is a 1 chain structure with sequence from Rattus norvegicus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.25Å Ligands: , , Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function CAN1_RAT Calcium-regulated non-lysosomal thiol-protease which catalyze limited proteolysis of substrates involved in cytoskeletal remodeling and signal transduction. Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMed 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. 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 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Calpain 3D structures

spinqualitylabelsall models 2g8e, resolution 2.25Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image