3K5D

Crystal Structure of BACE-1 in complex with AHM178

Summary for 3K5D

• Entry DOI: 10.2210/pdb3k5d/pdb
• Related PRD ID: PRD_000675
• Descriptor: Beta-secretase 1, N-acetyl-L-leucyl-N-[(4S,5S,7R)-8-(butylamino)-5-hydroxy-2,7-dimethyl-8-oxooctan-4-yl]-L-methioninamide (3 entities in total)
• Functional Keywords: aspartyl protease, alzheimer's disease, endoplasmic reticulum, endosome, glycoprotein, golgi apparatus, membrane, protease, transmembrane, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Membrane; Single-pass type I membrane protein: P56817
• Total number of polymer chains: 3
• Total formula weight: 137939.24

Authors

Rondeau, J.-M. (deposition date: 2009-10-07, release date: 2010-05-05, Last modification date: 2024-11-06)

Primary citation

Hanessian, S.,Shao, Z.,Betschart, C.,Rondeau, J.M.,Neumann, U.,Tintelnot-Blomley, M.
Structure-based design and synthesis of novel P2/P3 modified, non-peptidic beta-secretase (BACE-1) inhibitors.
Bioorg.Med.Chem.Lett., 20:1924-1927, 2010

PubMed Abstract: Starting from peptidomimetic BACE-1 inhibitors, the P2 amino acid including the P2/P3 peptide bond was replaced by a rigid 3-aminomethyl cyclohexane carboxylic acid. Co-crystallization revealed an unexpected binding mode with the P3/P4 amide bond placed into the S3 pocket resulting in a new hydrogen bond interaction pattern. Further optimization based on this structure resulted in highly potent BACE-1 inhibitors with selectivity over BACE-2 and cathepsin D.

PubMed: 20172717
DOI: 10.1016/j.bmcl.2010.01.139

Experimental method

X-RAY DIFFRACTION (2.9 Å)