Prev. Article Next Article Table of Contents

Article

Flap Position of Free Memapsin 2 (β-Secretase), a Model for Flap Opening in Aspartic Protease Catalysis^†^,^‡

Lin Hong^§ and Jordan Tang*^§^#

Protein Studies Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma 73104, Zapaq Incorporated, Oklahoma City, Oklahoma 73104, and Department of Biochemistry and Molecular Biology, University of Oklahoma Health Science Center, Oklahoma City, Oklahoma 73104

Biochemistry, 2004, 43 (16), pp 4689–4695

DOI: 10.1021/bi0498252

Publication Date (Web): April 1, 2004

†

This study was supported by National Institute of Health (Grant AG-18933) and Alzheimer's Association Pioneer Award to J.T.

‡

The atomic coordinates of the free memapsin 2 structure have been deposited in the Protein Data Bank (1SGZ).

Oklahoma Medical Research Foundation.

Zapaq Inc.

To whom correspondence should be addressed. E-mail: jordan-tang@omrf.ouhsc.edu.

University of Oklahoma Health Science Center.

Abstract

The three-dimensional structure of unbound human memapsin 2 (β-secretase) protease domain determined at 2.0-Å 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 Å 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 Å 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.

View: Full Text HTML | Hi-Res PDF

Tools

SciFinder Links

Accession Codes

History

Published In Issue April 27, 2004
Received January 23, 2004
Revised Manuscript Received February 24, 2004

Recommend & Share

Related Content

2-Amino-3,4-dihydroquinazolines as Inhibitors of BACE-1 (β-Site APP Cleaving Enzyme): Use of Structure Based Design to Convert a Micromolar Hit into a Nanomolar LeadJournal of Medicinal Chemistry
- 2-Amino-3,4-dihydroquinazolines as Inhibitors of BACE-1 (β-Site APP Cleaving Enzyme): Use of Structure Based Design to Convert a Micromolar Hit into a Nanomolar Lead
  Ellen W. Baxter, Kelly A. Conway, Ludo Kennis, François Bischoff, Marc H. Mercken, Hans L. De Winter, Charles H. Reynolds, Brett A. Tounge, Chi Luo, Malcolm K. Scott, Yifang Huang, Mirielle Braeken, Serge M. A. Pieters, Didier J. C. Berthelot, Stefan Masure, Wouter D. Bruinzeel, Alfonzo D. Jordan, Michael H. Parker, Robert E. Boyd, Junya Qu, Richard S. Alexander, Douglas E. Brenneman, and Allen B. Reitz
  Journal of Medicinal Chemistry 2007 50 (18), pp 4261–4264
  Abstract: A new aspartic protease inhibitory chemotype bearing a 2-amino-3,4-dihydroquinazoline ring was identified by high-throughput screening for the inhibition of BACE-1. X-ray crystallography revealed that the exocyclic amino group participated in a hydrogen ...
  Abstract | Full Text HTML | Hi-Res PDF
Crystal Structure of Memapsin 2 (β-Secretase) in Complex with an Inhibitor OM00-3Biochemistry
- Crystal Structure of Memapsin 2 (β-Secretase) in Complex with an Inhibitor OM00-3
  Lin Hong, Robert T. Turner, III, Gerald Koelsch, Dongoo Shin, Arun K. Ghosh, and Jordan Tang
  Biochemistry 2002 41 (36), pp 10963–10967
  Abstract: The structure of the catalytic domain of human memapsin 2 bound to an inhibitor OM00-3 (Glu-Leu-Asp-Leu*Ala-Val-Glu-Phe, K_i = 0.3 nM, the asterisk denotes the hydroxyethylene transition-state isostere) has been determined at 2.1 Å resolution. Uniquely ...
  Abstract | Full Text HTML | Hi-Res PDF
Identification of a Small Molecule Nonpeptide Active Site β-Secretase Inhibitor That Displays a Nontraditional Binding Mode for Aspartyl ProteasesJournal of Medicinal Chemistry
- Identification of a Small Molecule Nonpeptide Active Site β-Secretase Inhibitor That Displays a Nontraditional Binding Mode for Aspartyl Proteases
  Craig A. Coburn, Shawn J. Stachel, Yue-Ming Li, Diane M. Rush, Thomas G. Steele, Elizabeth Chen-Dodson, M. Katharine Holloway, Min Xu, Qian Huang, Ming-Tain Lai, Jillian DiMuzio, Ming-Chih Crouthamel, Xiao-Ping Shi, Vinod Sardana, Zhongguo Chen, Sanjeev Munshi, Lawrence Kuo, Gergely M. Makara, D. Allen Annis, Praveen K. Tadikonda, Huw M. Nash, Joseph P. Vacca, and Tong Wang
  Journal of Medicinal Chemistry 2004 47 (25), pp 6117–6119
  Abstract: A small molecule nonpeptide inhibitor of β-secretase has been developed, and its binding has been defined through crystallographic determination of the enzyme−inhibitor complex. The molecule is shown to bind to the catalytic aspartate residues in an ...
  Abstract | Full Text HTML | Hi-Res PDF

Article

Flap Position of Free Memapsin 2 (β-Secretase), a Model for Flap Opening in Aspartic Protease Catalysis^†^,^‡