2VKM

Crystal structure of GRL-8234 bound to BACE (Beta-secretase)

Summary for 2VKM

• Entry DOI: 10.2210/pdb2vkm/pdb
• Related: 1FKN 1M4H 1PY1 1SGZ 1TQF 1UJJ 1UJK 1W50 1W51 1XN2 1XN3 1XS7 1YM2 1YM4 2B8L 2B8V 2VA5 2VA6 2VA7 2VIE 2VIJ 2VIY 2VIZ 2VJ6 2VJ7
• Descriptor: BETA-SECRETASE 1, N-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-5-[methyl(methylsulfonyl)amino]-N'-[(1R)-1-phenylethyl]benzene-1,3-dicarboxamide (3 entities in total)
• Functional Keywords: alternative splicing, aspartyl protease, aspartic protease, glycoprotein, transmembrane, beta secretase, app, bace, a-beta, x- ray, zymogen, membrane, protease, memapsin, hydrolase, alzheimer, drug design
• Biological source: HOMO SAPIENS (HUMAN)
• Cellular location: Membrane; Single-pass type I membrane protein: P56817
• Total number of polymer chains: 4
• Total formula weight: 175886.45

Authors

Hong, L.,Tang, J.,Ghosh, A.K. (deposition date: 2007-12-04, release date: 2008-12-16, Last modification date: 2024-10-09)

Primary citation

Ghosh, A.K.,Kumaragurubaran, N.,Hong, L.,Kulkarni, S.,Xu, X.,Miller, H.B.,Reddy, D.S.,Weerasena, V.,Turner, R.,Chang, W.,Koelsch, G.,Tang, J.
Potent Memapsin 2 (Beta-Secretase) Inhibitors: Design, Synthesis, Protein-Ligand X-Ray Structure, and in Vivo Evaluation.
Bioorg.Med.Chem.Lett., 18:1031-, 2008

PubMed Abstract: Structure-based design, synthesis, and biological evaluation of a series of peptidomimetic beta-secretase inhibitors incorporating hydroxyethylamine isosteres are described. We have identified inhibitor 24 which has shown exceedingly potent activity in memapsin 2 enzyme inhibitory (K(i) 1.8 nM) and cellular (IC(50)=1 nM in Chinese hamster ovary cells) assays. Inhibitor 24 has also shown very impressive in vivo properties (up to 65% reduction of plasma A beta) in transgenic mice. The X-ray structure of protein-ligand complex of memapsin 2 revealed critical interactions in the memapsin 2 active site.

PubMed: 18180160
DOI: 10.1016/J.BMCL.2007.12.028

Experimental method

X-RAY DIFFRACTION (2.05 Å)