1YM4

Crystal structure of human beta secretase complexed with NVP-AMK640

Summary for 1YM4

• Entry DOI: 10.2210/pdb1ym4/pdb
• Related: 1YM2
• Related PRD ID: PRD_000292
• Descriptor: Beta-secretase 1, NVP-AMK640 INHIBITOR (3 entities in total)
• Functional Keywords: beta-secretase, memapsin2, alzheimer's disease, aspartic protease, hydrolase, 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: 6
• Total formula weight: 138233.09

Authors

Hanessian, S.,Yun, H.,Hou, Y.,Yang, G.,Bayrakdarian, M.,Therrien, E.,Moitessier, N.,Roggo, S.,Veenstra, S. (deposition date: 2005-01-20, release date: 2006-01-17, Last modification date: 2024-11-20)

Primary citation

Hanessian, S.,Yun, H.,Hou, Y.,Yang, G.,Bayrakdarian, M.,Therrien, E.,Moitessier, N.,Roggo, S.,Veenstra, S.,Tintelnot-Blomley, M.,Rondeau, J.M.,Ostermeier, C.,Strauss, A.,Ramage, P.,Paganetti, P.,Neumann, U.,Betschart, C.
Structure-based design, synthesis, and memapsin 2 (BACE) inhibitory activity of carbocyclic and heterocyclic peptidomimetics
J.Med.Chem., 48:5175-5190, 2005

PubMed Abstract: Molecular modeling based on the X-ray crystal structure of the Tang-Ghosh heptapeptide inhibitor 1 (OM99-2) of BACE led to the design and synthesis of a series of constrained P(1)' analogues. A cyclopentane ring was incorporated in 1 spanning the P(1)' Ala methyl group and the adjacent methylene carbon atom of the chain. Progressive truncation at the P(2)'-P(4)' sites led to a potent truncated analogue 5 with good selectivity over Cathepsin D. Using the same backbone replacement concept, a series of cyclopentane, cyclopentanone, tetrahydrofuran, pyrrolidine, and pyrrolidinone analogues were synthesized with considerable variation at the P and P' sites. The cyclopentanone and 2-pyrrolidinone analogues 45 and 57 showed low nM BACE inhibition. X-ray cocrystal structures of two analogues 5 and 45 revealed excellent convergence with the original inhibitor 1 structure while providing new insights into other interactions which could be exploited for future modifications.

PubMed: 16078837
DOI: 10.1021/jm050142+

Experimental method

X-RAY DIFFRACTION (2.25 Å)