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PDBsum entry 2tsc
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Transferase (methyltransferase)
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PDB id
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2tsc
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Contents |
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* Residue conservation analysis
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References listed in PDB file
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Key reference
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Title
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Structure, Multiple site binding, And segmental accommodation in thymidylate synthase on binding dump and an anti-Folate.
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Authors
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W.R.Montfort,
K.M.Perry,
E.B.Fauman,
J.S.Finer-Moore,
G.F.Maley,
L.Hardy,
F.Maley,
R.M.Stroud.
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Ref.
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Biochemistry, 1990,
29,
6964-6977.
[DOI no: ]
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PubMed id
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Abstract
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The structure of Escherichia coli thymidylate synthase (TS) complexed with the
substrate dUMP and an analogue of the cofactor methylenetetrahydrofolate was
solved by multiple isomorphous replacement and refined at 1.97-A resolution to a
residual of 18% for all data (16% for data greater than 2 sigma) for a highly
constrained structure. All residues in the structure are clearly resolved and
give a very high confidence in total correctness of the structure. The ternary
complex directly suggests how methylation of dUMP takes place. C-6 of dUMP is
covalently bound to gamma S of Cys-198(146) during catalysis, and the reactants
are surrounded by specific hydrogen bonds and hydrophobic interactions from
conserved residues. Comparison with the independently solved structure of
unliganded TS reveals a large conformation change in the enzyme, which closes
down to sequester the reactants and several highly ordered water molecules
within a cavernous active center, away from bulk solvent. A second binding site
for the quinazoline ring of the cofactor analogue was discovered by withholding
addition of reducing agent during crystal storage. The chemical change in the
protein is slight, and from difference density maps modification of sulfhydryls
is not directly responsible for blockade of the primary site. The site, only
partially overlapping with the primary site, is also surrounded by conserved
residues and thus may play a functional role. The ligand-induced conformational
change is not a domain shift but involves the segmental accommodation of several
helices, beta-strands, and loops that move as units against the beta-sheet
interface between monomers.
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Secondary reference #1
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Title
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Pairwise specificity and sequential binding in enzyme catalysis: thymidylate synthase.
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Authors
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J.S.Finer-Moore,
W.R.Montfort,
R.M.Stroud.
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Ref.
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Biochemistry, 1990,
29,
6977-6986.
[DOI no: ]
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PubMed id
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Secondary reference #2
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Title
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Plastic adaptation toward mutations in proteins: structural comparison of thymidylate synthases.
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Authors
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K.M.Perry,
E.B.Fauman,
J.S.Finer-Moore,
W.R.Montfort,
G.F.Maley,
F.Maley,
R.M.Stroud.
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Ref.
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Proteins, 1990,
8,
315-333.
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PubMed id
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