Crystal structure of memapsin 2 (β-secretase) in complex with an inhibitor OM00-3

被引：178

作者：

Hong, L

Turner, RT

Koelsch, G

Shin, DG

Ghosh, AK

Tang, J ^{[1
]}

机构：

[1] Univ Oklahoma, Ctr Med, Prot Studies Program, Oklahoma Med Res Fdn, Oklahoma City, OK 73104 USA

[2] Univ Oklahoma, Ctr Med, Prot Studies Program, Dept Biochem & Mol Biol, Oklahoma City, OK 73104 USA

[3] Zapaq Inc, Oklahoma City, OK 73104 USA

[4] Univ Illinois, Dept Chem, Chicago, IL 60607 USA

来源：

BIOCHEMISTRY | 2002年 / 41卷 / 36期

关键词：

D O I：

10.1021/bi026232n

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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 Angstrom 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-Leu*Ala-Ala-Glu-Phe, Ki = I 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'.

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页码：10963 / 10967

页数：5

相关论文

共 19 条

[1] Crystallography & NMR system:: A new software suite for macromolecular structure determination [J].

Brunger, AT ;

Adams, PD ;

Clore, GM ;

DeLano, WL ;

Gros, P ;

Grosse-Kunstleve, RW ;

Jiang, JS ;

Kuszewski, J ;

Nilges, M ;

Pannu, NS ;

Read, RJ ;

Rice, LM ;

Simonson, T ;

Warren, GL .

ACTA CRYSTALLOGRAPHICA SECTION D-BIOLOGICAL CRYSTALLOGRAPHY, 1998, 54 :905-921

[2] BACE1 is the major β-secretase for generation of Aβ peptides by neurons [J].

Cai, HB ;

Wang, YS ;

McCarthy, D ;

Wen, HJ ;

Borchelt, DR ;

Price, DL ;

Wong, PC .

NATURE NEUROSCIENCE, 2001, 4 (03) :233-234

[3] Proteolytic activation of recombinant pro-memapsin 2 (pro-β-secretase) studied with new fluorogenic substrates [J].

Ermolieff, J ;

Loy, JA ;

Koelsch, G ;

Tang, J .

BIOCHEMISTRY, 2000, 39 (40) :12450-12456

[4] Design of potent inhibitors for human brain memapsin 2 (β-secretase) [J].

Ghosh, AK ;

Shin, DW ;

Downs, D ;

Koelsch, G ;

Lin, XL ;

Ermolieff, J ;

Tang, J .

JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 2000, 122 (14) :3522-3523

[5] Structure-based design:: Potent inhibitors of human brain memapsin 2 (β-secretase) [J].

Ghosh, AK ;

Bilcer, G ;

Harwood, C ;

Kawahama, R ;

Shin, D ;

Hussain, KA ;

Hong, L ;

Loy, JA ;

Nguyen, C ;

Koelsch, G ;

Ermolieff, J ;

Tang, J .

JOURNAL OF MEDICINAL CHEMISTRY, 2001, 44 (18) :2865-2868

[6] Structure of the protease domain of memapsin 2 (β-secretase) complexed with inhibitor [J].

Hong, L ;

Koelsch, G ;

Lin, XL ;

Wu, SL ;

Terzyan, S ;

Ghosh, AK ;

Zhang, XC ;

Tang, J .

SCIENCE, 2000, 290 (5489) :150-153

[7] Identification of a novel aspartic protease (Asp 2) as β-secretase [J].

Hussain, I ;

Powell, D ;

Howlett, DR ;

Tew, DG ;

Week, TD ;

Chapman, C ;

Gloger, IS ;

Murphy, KE ;

Southan, CD ;

Ryan, DM ;

Smith, TS ;

Simmons, DL ;

Walsh, FS ;

Dingwall, C ;

Christie, G .

MOLECULAR AND CELLULAR NEUROSCIENCE, 1999, 14 (06) :419-427

[8] IMPROVED METHODS FOR BUILDING PROTEIN MODELS IN ELECTRON-DENSITY MAPS AND THE LOCATION OF ERRORS IN THESE MODELS [J].

JONES, TA ;

ZOU, JY ;

COWAN, SW ;

KJELDGAARD, M .

ACTA CRYSTALLOGRAPHICA SECTION A, 1991, 47 :110-119

[9] Human aspartic protease memapsin 2 cleaves the β-secretase site of β-amyloid precursor protein [J].

Lin, XL ;

Koelsch, C ;

Wu, SL ;

Downs, D ;

Dashti, A ;

Tang, J .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2000, 97 (04) :1456-1460

[10] Mice deficient in BACE1, the Alzheimer's β-secretase, have normal phenotype and abolished β-amyloid generation [J].

Luo, Y ;

Bolon, B ;

Kahn, S ;

Bennett, BD ;

Babu-Khan, S ;

Denis, P ;

Fan, W ;

Kha, H ;

Zhang, JH ;

Gong, YH ;

Martin, L ;

Louis, JC ;

Yan, Q ;

Richards, WG ;

Citron, M ;

Vassar, R .

NATURE NEUROSCIENCE, 2001, 4 (03) :231-232