1SGZ

Crystal Structure of Unbound Beta-Secretase Catalytic Domain.

Summary for 1SGZ

• Entry DOI: 10.2210/pdb1sgz/pdb
• Related: 1FKN 1M4H
• Descriptor: Beta-secretase (2 entities in total)
• Functional Keywords: beta-secretase, memapsin, bace, aspartic protease, protease flap, drug design, asp2, alzheimer's disease, hydrolase
• Biological source: Homo sapiens (human)
• Cellular location: Membrane; Single-pass type I membrane protein: P56817
• Total number of polymer chains: 4
• Total formula weight: 173251.22

Authors

Hong, L.,Tang, J. (deposition date: 2004-02-24, release date: 2004-05-04, Last modification date: 2023-08-23)

Primary citation

Hong, L.,Tang, J.
Flap Position of Free Memapsin 2 (beta-Secretase), a Model for Flap Opening in Aspartic Protease Catalysis
Biochemistry, 43:4689-4695, 2004

PubMed Abstract: The three-dimensional structure of unbound human memapsin 2 (beta-secretase) protease domain determined at 2.0-A resolution has revealed a new position of the flap region, which appears to be locked in an "open" position. While the structure outside of the flap is essentially the same as the structure of memapsin 2 bound to an inhibitor, the flap positions are 4.5 A different at the tips. The open position of the flap in the current structure is stabilized by two newly formed intraflap hydrogen bonds and anchored by a new hydrogen bond involving the side chain of Tyr 71 (Tyr 75 in pepsin numbering) in a novel orientation. In molecular modeling experiments, the opening of the flap, 6.5 A at the narrowest point, permits entrance of substrates into the cleft. The narrowest point of the opening may function to discriminate among substrates based on sequence and shape. The observed flap opening may also serve as a model for the flap movement in the catalytic mechanism of eukaryotic aspartic proteases and provide insight for the side-chain selection in the design of memapsin 2 inhibitors.

PubMed: 15096037
DOI: 10.1021/bi0498252

Experimental method

X-RAY DIFFRACTION (2 Å)