4TRW

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

Summary for 4TRW

• Entry DOI: 10.2210/pdb4trw/pdb
• Related: 4TRY 4TRZ
• Related PRD ID: PRD_002103
• Descriptor: Beta-secretase 1, L-alpha-glutamyl-L-isoleucyl-N-[(2R,3S)-1-{[(1S)-1-carboxybutyl]amino}-2-hydroxy-5-methylhexan-3-yl]-3-thiophen-2-yl-L-alaninamide (3 entities in total)
• Functional Keywords: hydrase proteinase converting, designed inhibitor, hydrase-inhibitor complex, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 6
• Total formula weight: 132203.34

Authors

Akaji, K.,Teruya, K.,Akiyama, T.,Sanjho, A.,Yamashita, E.,Nakagawa, A. (deposition date: 2014-06-18, release date: 2015-07-01, Last modification date: 2024-10-30)

Primary citation

Hattori, Y.,Kobayashi, K.,Deguchi, A.,Nohara, Y.,Akiyama, T.,Teruya, K.,Sanjoh, A.,Nakagawa, A.,Yamashita, E.,Akaji, K.
Evaluation of transition-state mimics in a superior BACE1 cleavage sequence as peptide-mimetic BACE1 inhibitors
Bioorg.Med.Chem., 23:5626-5640, 2015

PubMed Abstract: 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.

PubMed: 26264846
DOI: 10.1016/j.bmc.2015.07.023

Experimental method

X-RAY DIFFRACTION (2.85 Å)