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PDBsum entry 4gtc
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References listed in PDB file
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Key reference
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Title
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Folate binding site of flavin-Dependent thymidylate synthase.
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Authors
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E.M.Koehn,
L.L.Perissinotti,
S.Moghram,
A.Prabhakar,
S.A.Lesley,
I.I.Mathews,
A.Kohen.
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Ref.
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Proc Natl Acad Sci U S A, 2012,
109,
15722-15727.
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PubMed id
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Abstract
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The DNA nucleotide thymidylate is synthesized by the enzyme thymidylate
synthase, which catalyzes the reductive methylation of deoxyuridylate using the
cofactor methylene-tetrahydrofolate (CH(2)H(4)folate). Most organisms, including
humans, rely on the thyA- or TYMS-encoded classic thymidylate synthase, whereas,
certain microorganisms, including all Rickettsia and other pathogens, use an
alternative thyX-encoded flavin-dependent thymidylate synthase (FDTS). Although
several crystal structures of FDTSs have been reported, the absence of a
structure with folates limits understanding of the molecular mechanism and the
scope of drug design for these enzymes. Here we present X-ray crystal structures
of FDTS with several folate derivatives, which together with mutagenesis,
kinetic analysis, and computer modeling shed light on the cofactor binding and
function. The unique structural data will likely facilitate further elucidation
of FDTSs' mechanism and the design of structure-based inhibitors as potential
leads to new antimicrobial drugs.
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