Inhibitor-bound complexes of dihydrofolate reductase-thymidylate synthase from Babesia bovis

被引：16

作者：

Begley, Darren W. ^{[1
,2
]}

Edwards, Thomas E. ^{[1
,2
]}

Raymond, Amy C. ^{[1
,2
]}

Smith, Eric R. ^{[1
,2
]}

Hartley, Robert C. ^{[1
,2
]}

Abendroth, Jan ^{[1
,2
]}

Sankaran, Banumathi ^{[3
]}

Lorimer, Donald D. ^{[1
,2
]}

Myler, Peter J. ^{[1
,4
,5
,6
,7
]}

Staker, Bart L. ^{[1
,2
]}

Stewart, Lance J. ^{[1
,2
]}

机构：

[1] Seattle Struct Genom Ctr Infect Dis, Seattle, WA 98125 USA

[2] Emerald BioStruct Inc, Bainbridge Isl, WA 98110 USA

[3] Berkeley Ctr Struct Biol, Berkeley, CA 94720 USA

[4] Seattle BioMed, Seattle, WA 98109 USA

[5] Univ Washington, Sch Med, Dept Global Hlth, Seattle, WA 98195 USA

[6] Univ Washington, Sch Med, Dept Med Educ, Seattle, WA 98195 USA

[7] Univ Washington, Sch Med, Dept Biomed Informat, Seattle, WA 98195 USA

来源：

ACTA CRYSTALLOGRAPHICA SECTION F-STRUCTURAL BIOLOGY COMMUNICATIONS | 2011年 / 67卷

基金：

美国国家卫生研究院;

关键词：

PROTEIN CRYSTALLIZATION SYSTEM; CRYPTOSPORIDIUM-HOMINIS; ANTIFOLATE RESISTANCE; CRYSTAL-STRUCTURE; DIFFRACTION DATA; CELL-GROWTH; DATA-BANK; ACID; DRUG; CRYSTALLOGRAPHY;

D O I：

10.1107/S1744309111029009

中图分类号：

Q5 [生物化学];

学科分类号：

071010 ; 081704 ;

摘要：

Babesiosis is a tick-borne disease caused by eukaryotic Babesia parasites which are morphologically similar to Plasmodium falciparum, the causative agent of malaria in humans. Like Plasmodium, different species of Babesia are tuned to infect different mammalian hosts, including rats, dogs, horses and cattle. Most species of Plasmodium and Babesia possess an essential bifunctional enzyme for nucleotide synthesis and folate metabolism: dihydrofolate reductase-thymidylate synthase. Although thymidylate synthase is highly conserved across organisms, the bifunctional form of this enzyme is relatively uncommon in nature. The structural characterization of dihydrofolate reductase-thymidylate synthase in Babesia bovis, the causative agent of babesiosis in livestock cattle, is reported here. The apo state is compared with structures that contain dUMP, NADP and two different antifolate inhibitors: pemetrexed and raltitrexed. The complexes reveal modes of binding similar to that seen in drug-resistant malaria strains and point to the utility of applying structural studies with proven cancer chemotherapies towards infectious disease research.

引用

页码：1070 / 1077

页数：8

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