2G94

Crystal structure of beta-secretase bound to a potent and highly selective inhibitor.

Summary for 2G94

• Entry DOI: 10.2210/pdb2g94/pdb
• Descriptor: Beta-secretase 1, N~2~-[(2R,4S,5S)-5-{[N-{[(3,5-DIMETHYL-1H-PYRAZOL-1-YL)METHOXY]CARBONYL}-3-(METHYLSULFONYL)-L-ALANYL]AMINO}-4-HYDROXY-2,7-DIMETHYLOCTANOYL]-N-ISOBUTYL-L-VALINAMIDE (3 entities in total)
• Functional Keywords: beta secretase, alzheimer's disease, memapsin, bace, asp2, aspartic protease, drug design, protease inhibitor, hydrolase
• Biological source: Homo sapiens (human)
• Cellular location: Membrane; Single-pass type I membrane protein: P56817
• Total number of polymer chains: 4
• Total formula weight: 175886.62

Authors

Hong, L.,Ghosh, A.,Tang, J. (deposition date: 2006-03-05, release date: 2006-04-25, Last modification date: 2024-10-30)

Primary citation

Ghosh, A.K.,Kumaragurubaran, N.,Hong, L.,Lei, H.,Hussain, K.A.,Liu, C.F.,Devasamudram, T.,Weerasena, V.,Turner, R.,Koelsch, G.,Bilcer, G.,Tang, J.
Design, synthesis and X-ray structure of protein-ligand complexes: important insight into selectivity of memapsin 2 (beta-secretase) inhibitors.
J.Am.Chem.Soc., 128:5310-5311, 2006

PubMed Abstract: Structure-based design, synthesis, and X-ray structure of protein-ligand complexes of memapsin 2 are described. The inhibitors are designed specifically to interact with S2- and S3-active site residues to provide selectivity over memapsin 1 and cathepsin D. Inhibitor 6 has exhibited exceedingly potent inhibitory activity against memapsin 2 and selectivity over memapsin 1 (>3800-fold) and cathepsin D (>2500-fold). A protein-ligand crystal structure revealed cooperative interactions in the S2- and S3-active sites of memapsin 2. These interactions may serve as an important guide to design selectivity over memapsin 1 and cathepsin D.

PubMed: 16620080
DOI: 10.1021/ja058636j

Experimental method

X-RAY DIFFRACTION (1.86 Å)