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Title
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Solution structure of the active domain of tissue inhibitor of metalloproteinases-2. A new member of the OB fold protein family.
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Authors
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R.A.Williamson,
G.Martorell,
M.D.Carr,
G.Murphy,
A.J.Docherty,
R.B.Freedman,
J.Feeney.
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Ref.
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Biochemistry, 1994,
33,
11745-11759.
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PubMed id
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Abstract
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Homonuclear two-dimensional and three-dimensional 1H nuclear magnetic resonance
spectroscopy has been used to obtain essentially complete sequence-specific
assignments for 123 of the 127 amino acid residues present in the truncated form
of tissue inhibitor of metalloproteinases-2 (delta TIMP-2), the active
N-terminal domain of the protein. Analysis of the through-space nuclear
Overhauser effect data obtained for delta TIMP-2 allowed determination of both
the secondary structure of the domain and also a low-resolution tertiary
structure defining the protein backbone topology. The protein contains a
five-stranded antiparallel beta-sheet that is rolled over on itself to form a
closed beta-barrel, and two short helices which pack close to one another on the
same barrel face. A comparison of the delta TIMP-2 structure with other known
protein folds reveals that the beta-barrel topology is homologous to that seen
in proteins of the oligosaccharide/oligonucleotide binding (OB) fold family. The
common structural features include the number of beta-strands and their
arrangement, the beta-barrel shear number, an interstrand hydrogen bond network,
the packing of the hydrophobic core, and a conserved beta-bulge. Superpositions
of the beta-barrels from delta TIMP-2 and two previously known members of the OB
protein fold family (staphylococcal nuclease and Escherichia coli heat-labile
enterotoxin) confirmed the similarity in beta-barrel topology. The
three-dimensional structure of delta TIMP-2 has allowed a more detailed
interpretation than was previously possible of the functional significance of
available protein sequence and site-directed mutagenesis data for the TIMP
family. Furthermore, the structure has revealed conserved surface regions of
potential functional importance.
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