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PDBsum entry 2fit
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Chromosomal translocation
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PDB id
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2fit
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References listed in PDB file
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Key reference
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Title
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Mad analysis of fhit, A putative human tumor suppressor from the hit protein family.
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Authors
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C.D.Lima,
K.L.D'Amico,
I.Naday,
G.Rosenbaum,
E.M.Westbrook,
W.A.Hendrickson.
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Ref.
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Structure, 1997,
5,
763-774.
[DOI no: ]
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PubMed id
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Abstract
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BACKGROUND: The fragile histidine triad (FHIT) protein is a member of the large
and ubiquitous histidine triad (HIT) family of proteins. It is expressed from a
gene located at a fragile site on human chromosome 3, which is commonly
disrupted in association with certain cancers. On the basis of the genetic
evidence, it has been postulated that the FHIT protein may function as a tumor
suppressor, implying a role for the FHIT protein in carcinogenesis. The FHIT
protein has dinucleoside polyphosphate hydrolase activity in vitro, thus
suggesting that its role in vivo may involve the hydrolysis of a
phosphoanhydride bond. The structural analysis of FHIT will identify critical
residues involved in substrate binding and catalysis, and will provide insights
into the in vivo function of HIT proteins. RESULTS: The three-dimensional
crystal structures of free and nucleoside complexed FHIT have been determined
from multiwavelength anomalous diffraction (MAD) data, and they represent some
of the first successful structures to be measured with undulator radiation at
the Advanced Photon Source. The structures of FHIT reveal that this protein
exists as an intimate homodimer, which is based on a core structure observed
previously in another human HIT homolog, protein kinase C interacting protein
(PKCI), but has distinctive elaborations at both the N and C termini. Conserved
residues within the HIT family, which are involved in the interactions of the
proteins with nucleoside and phosphate groups, appear to be relevant for the
catalytic activity of this protein. CONCLUSIONS: The structure of FHIT, a
divergent HIT protein family member, in complex with a nucleotide analog
suggests a metal-independent catalytic mechanism for the HIT family of proteins.
A structural comparison of FHIT with PKCI and galactose-1-phosphate
uridylyltransferase (GaIT) reveals additional implications for the structural
and functional evolution of the ubiquitous HIT family of proteins.
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Figure 5.
Figure 5. Schematic stereo diagram of FHIT in
adenosine/sulfate product complexed form. Hydrogen-bonding
interactions thought to be important in catalysis and ligand
recognition are depicted by dotted lines. To simplify the
depiction, only a subset of residues have been shown
superimposed on the Ca backbone spline. Although most residues
involved in interactions between protein and adenine base are
not conserved between FHIT and PKCI (not shown here), both
proteins utilize a deep hydrophobic cleft and water-mediated
contacts to the backbone of N-terminal residues in binding the
adenosine base.
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The above figure is
reprinted
by permission from Cell Press:
Structure
(1997,
5,
763-774)
copyright 1997.
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