1M4H

Crystal Structure of Beta-secretase complexed with Inhibitor OM00-3

Summary for 1M4H

• Entry DOI: 10.2210/pdb1m4h/pdb
• Related PRD ID: PRD_000289
• Descriptor: beta-Secretase, Inhibitor OM00-3 (3 entities in total)
• Functional Keywords: memapsin2, base, asp2, alzheimer's disease, aspartic protease, acid protease, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Homo sapiens (human); More
• Cellular location: Membrane; Single-pass type I membrane protein: P56817
• Total number of polymer chains: 4
• Total formula weight: 89126.50

Authors

Hong, L.,Turner, R.T.,Koelsch, G.,Ghosh, A.K.,Tang, J. (deposition date: 2002-07-02, release date: 2002-08-28, Last modification date: 2024-11-20)

Primary citation

Hong, L.,Turner, R.T.,Koelsch, G.,Shin, D.,Ghosh, A.K.,Tang, J.
Crystal Structure of Memapsin 2 (beta-Secretase) in Complex with Inhibitor OM00-3
Biochemistry, 41:10963-10967, 2002

PubMed Abstract: The structure of the catalytic domain of human memapsin 2 bound to an inhibitor OM00-3 (Glu-Leu-Asp-LeuAla-Val-Glu-Phe, K(i) = 0.3 nM, the asterisk denotes the hydroxyethylene transition-state isostere) has been determined at 2.1 A resolution. Uniquely defined in the structure are the locations of S(3)' and S(4)' subsites, which were not identified in the previous structure of memapsin 2 in complex with the inhibitor OM99-2 (Glu-Val-Asn-LeuAla-Ala-Glu-Phe, K(i) = 1 nM). Different binding modes for the P(2) and P(4) side chains are also observed. These new structural elements are useful for the design of new inhibitors. The structural and kinetic data indicate that the replacement of the P(2)' alanine in OM99-2 with a valine in OM00-3 stabilizes the binding of P(3)' and P(4)'.

PubMed: 12206667
DOI: 10.1021/bi026232n

Experimental method

X-RAY DIFFRACTION (2.1 Å)