Two crystal structures of dihydrofolate reductase-thymidylate synthase from Cryptosporidium hominis reveal protein-ligand interactions including a structural basis for observed antifolate resistance

被引：27

作者：

Anderson, AC ^{[1
]}

机构：

[1] Dartmouth Coll, Dept Chem, Burke Labs, Hanover, NH 03755 USA

来源：

ACTA CRYSTALLOGRAPHICA SECTION F-STRUCTURAL BIOLOGY COMMUNICATIONS | 2005年 / 61卷

关键词：

D O I：

10.1107/S1744309105002435

中图分类号：

Q5 [生物化学];

学科分类号：

071010 ; 081704 ;

摘要：

Cryptosporidium hominis is a protozoan parasite that causes acute gastrointestinal illness. There are no effective therapies for cryptosporidiosis, highlighting the need for new drug-lead discovery. An analysis of the protein-ligand interactions in two crystal structures of dihydrofolate reductase-thymidylate synthase (DHFR-TS) from C. hominis, determined at 2.8 and 2.87 angstrom resolution, reveals that the interactions of residues Ile29, Thr58 and Cys113 in the active site of C. hominis DHFR provide a possible structural basis for the observed antifolate resistance. A comparison with the structure of human DHFR reveals active-site differences that may be exploited for the design of species-selective inhibitors.

引用

页码：258 / 262

页数：5

共 21 条

[1] THE CCP4 SUITE - PROGRAMS FOR PROTEIN CRYSTALLOGRAPHY [J].

BAILEY, S .

ACTA CRYSTALLOGRAPHICA SECTION D-BIOLOGICAL CRYSTALLOGRAPHY, 1994, 50 :760-763

[2] Plasmodium falciparum: Molecular characterization of multidrug-resistant Cambodian isolates [J].

Basco, LK ;

dePecoulas, PE ;

LeBras, J ;

Wilson, CM .

EXPERIMENTAL PARASITOLOGY, 1996, 82 (02) :97-103

[3]

Brunger AT, 1998, ACTA CRYSTALLOGR D, V54, P905, DOI 10.1107/s0907444998003254

[4] Ligand-induced conformational changes in the crystal structures of Pneumocystis carinii dihydrofolate reductase complexes with folate and NADP+ [J].

Cody, V ;

Galitsky, N ;

Rak, D ;

Luft, JR ;

Pangborn, W ;

Queener, SF .

BIOCHEMISTRY, 1999, 38 (14) :4303-4312

[5] AMINO-ACIDS IN THE DIHYDROFOLATE REDUCTASE-THYMIDYLATE SYNTHASE GENE OF PLASMODIUM-FALCIPARUM INVOLVED IN CYCLOGUANIL RESISTANCE DIFFER FROM THOSE INVOLVED IN PYRIMETHAMINE RESISTANCE [J].

FOOTE, SJ ;

GALATIS, D ;

COWMAN, AF .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1990, 87 (08) :3014-3017

[6] Cryptosporidiosis: Are emerging, highly infectious threat [J].

Guerrant, RL .

EMERGING INFECTIOUS DISEASES, 1997, 3 (01) :51-57

[7] RECEPTOR-BASED DESIGN OF DIHYDROFOLATE-REDUCTASE INHIBITORS - COMPARISON OF CRYSTALLOGRAPHICALLY DETERMINED ENZYME BINDING WITH ENZYME AFFINITY IN A SERIES OF CARBOXY-SUBSTITUTED TRIMETHOPRIM ANALOGS [J].

KUYPER, LF ;

ROTH, B ;

BACCANARI, DP ;

FERONE, R ;

BEDDELL, CR ;

CHAMPNESS, JN ;

STAMMERS, DK ;

DANN, JG ;

NORRINGTON, FE ;

BAKER, DJ ;

GOODFORD, PJ .

JOURNAL OF MEDICINAL CHEMISTRY, 1985, 28 (03) :303-311

[8] A subgroup algorithm to identify cross-rotation peaks consistent with non-crystallographic symmetry [J].

Lilien, RH ;

Bailey-Kellogg, C ;

Anderson, AC ;

Donald, BR .

ACTA CRYSTALLOGRAPHICA SECTION D-STRUCTURAL BIOLOGY, 2004, 60 :1057-1067

[9] Dicyclic and tricyclic diaminopyrimidine derivatives as potent inhibitors of Cryptosporidium parvum dihydrofolate reductase:: Structure-activity and structure-selectivity correlations [J].

Nelson, RG ;

Rosowsky, A .

ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, 2001, 45 (12) :3293-3303

[10] The crystal structure of dihydrofolate reductase-thymidylate synthase from Cryptosporidium hominis reveals a novel architecture for the bifunctional enzyme [J].

O'Neil, RH ;

Lilien, RH ;

Donald, BR ;

Stroud, RM ;

Anderson, AC .

JOURNAL OF EUKARYOTIC MICROBIOLOGY, 2003, 50 :555-556

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