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J. Biol. Chem., Vol. 278, Issue 52, 52980-52987, December 26, 2003

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Phylogenetic Classification of Protozoa Based on the Structure of the Linker Domain in the Bifunctional Enzyme, Dihydrofolate Reductase-Thymidylate Synthase^*

Robert H. O'Neil, Ryan H. Lilien, Bruce R. Donald, Robert M. Stroud¶, and Amy C. Anderson||

From the Departments of Chemistry and Computer Science, Dartmouth College, Hanover, New Hampshire 03755 and the ^¶Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, California 94143

We have determined the crystal structure of dihydrofolate reductase-thymidylate synthase (DHFR-TS) from Cryptosporidium hominis, revealing a unique linker domain containing an 11-residue -helix that has extensive interactions with the opposite DHFR-TS monomer of the homodimeric enzyme. Analysis of the structure of DHFR-TS from C. hominis and of previously solved structures of DHFR-TS from Plasmodium falciparum and Leishmania major reveals that the linker domain primarily controls the relative orientation of the DHFR and TS domains. Using the tertiary structure of the linker domains, we have been able to place a number of protozoa in two distinct and dissimilar structural families corresponding to two evolutionary families and provide the first structural evidence validating the use of DHFR-TS as a tool of phylogenetic classification. Furthermore, the structure of C. hominis DHFR-TS calls into question surface electrostatic channeling as the universal means of dihydrofolate transport between TS and DHFR in the bifunctional enzyme.

Received for publication, September 17, 2003 , and in revised form, October 6, 2003.

The atomic coordinates and structure factors (code 1QZF) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

^* This work was supported by National Institutes of Health (NIH) Grant GM067542 (to A. C. A.), NIH CA63081 (to R. M. S.), and NIH Grant GM65982 (to B. R. D.). Computer equipment for developing the quaternion algorithm was supported by National Science Foundation Grants 98-02068 and IIS-9906790 (to B. R. D.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^|| To whom correspondence should be addressed: Dept. of Chemistry, 6128 Burke Laboratories, Dartmouth College, Hanover, NH 03755. Tel.: 603-646-1154; Fax: 603-646-3946; E-mail: Amy.C.Anderson{at}Dartmouth.edu.

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				C. E. Atreya and K. S. Anderson Kinetic Characterization of Bifunctional Thymidylate Synthase-Dihydrofolate Reductase (TS-DHFR) from Cryptosporidium hominis: A PARADIGM SHIFT FOR TS ACTIVITY AND CHANNELING BEHAVIOR J. Biol. Chem., April 30, 2004; 279(18): 18314 - 18322. [Abstract] [Full Text] [PDF]