3K5F

Human BACE-1 COMPLEX WITH AYH011

Summary for 3K5F

• Entry DOI: 10.2210/pdb3k5f/pdb
• Related: 3K5C 3K5D 3K5G
• Descriptor: Beta-secretase 1, (1R,3S)-3-[1-(acetylamino)-1-methylethyl]-N-[(1S,2S,4R)-1-benzyl-5-(butylamino)-2-hydroxy-4-methyl-5-oxopentyl]cyclohexanecarboxamide (3 entities in total)
• Functional Keywords: aspartyl protease, alzheimer's disease, structure-based design, disulfide bond, endoplasmic reticulum, endosome, glycoprotein, golgi apparatus, hydrolase-hydrolase inhibitor complex, membrane, protease, transmembrane, 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: 135837.11

Authors

Rondeau, J.-M. (deposition date: 2009-10-07, release date: 2010-05-05, Last modification date: 2024-11-20)

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 (2.25 Å)