4trw

Structure of BACE1 complex with a syn-HEA-type inhibitorStructure of BACE1 complex with a syn-HEA-type inhibitor

Structural highlights 4trw is a 6 chain structure with sequence from Homo sapiens and Synthetic construct. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.85Å Ligands: , Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function BACE1_HUMAN Responsible for the proteolytic processing of the amyloid precursor protein (APP). Cleaves at the N-terminus of the A-beta peptide sequence, between residues 671 and 672 of APP, leads to the generation and extracellular release of beta-cleaved soluble APP, and a corresponding cell-associated C-terminal fragment which is later released by gamma-secretase. Publication Abstract from PubMed A superior substrate sequence for BACE1 containing transition-state mimics at the scissile site was evaluated as a protease inhibitor. Hydroxymethylcarbonyl (HMC) and hydroxyethylamine (HEA) isosteres were selected as the transition state mimics, and incorporated into the scissile site of the superior sequence covering the P4 to P1' sites (Glu-Ile-Thi-Thi(*)Nva; (*)denotes the cleavage site). Isosteres having different absolute configurations of the hydroxyl group were synthesized separately, and the effect of the configuration was evaluated. Configuration of the hydroxyl group of each isostere showed a marked effect on the inhibitory activity; anti-configuration to the scissile site substituent had potent inhibitory activity in an HMC-type inhibitor, whereas anti-configuration of HEA-type inhibitors showed no inhibitory activity. Structural evaluations based on X-ray crystallographic analyses of recombinant BACE1 in complex with each inhibitor provided insights into the protein-ligand interactions, especially at the prime sites. Evaluation of transition-state mimics in a superior BACE1 cleavage sequence as peptide-mimetic BACE1 inhibitors.,Hattori Y, Kobayashi K, Deguchi A, Nohara Y, Akiyama T, Teruya K, Sanjoh A, Nakagawa A, Yamashita E, Akaji K Bioorg Med Chem. 2015 Sep 1;23(17):5626-40. doi: 10.1016/j.bmc.2015.07.023. Epub , 2015 Jul 21. PMID:26264846 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Beta secretase 3D structures

spinqualitylabelsall models 4trw, resolution 2.85Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image