Linked Life Data

10080896

Source:http://linkedlifedata.com/resource/pubmed/id/10080896

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
2
pubmed:dateCreated
1999-4-28
pubmed:databankReference
pubmed:abstractText
Uracil-DNA glycosylase (UDG), which is a critical enzyme in DNA base-excision repair that recognizes and removes uracil from DNA, is specifically and irreversably inhibited by the thermostable uracil-DNA glycosylase inhibitor protein (Ugi). A paradox for the highly specific Ugi inhibition of UDG is how Ugi can successfully mimic DNA backbone interactions for UDG without resulting in significant cross-reactivity with numerous other enzymes that possess DNA backbone binding affinity. High-resolution X-ray crystal structures of Ugi both free and in complex with wild-type and the functionally defective His187Asp mutant Escherichia coli UDGs reveal the detailed molecular basis for duplex DNA backbone mimicry by Ugi. The overall shape and charge distribution of Ugi most closely resembles a midpoint in a trajectory between B-form DNA and the kinked DNA observed in UDG:DNA product complexes. Thus, Ugi targets the mechanism of uracil flipping by UDG and appears to be a transition-state mimic for UDG-flipping of uracil nucleotides from DNA. Essentially all the exquisite shape, electrostatic and hydrophobic complementarity for the high-affinity UDG-Ugi interaction is pre-existing, except for a key flip of the Ugi Gln19 carbonyl group and Glu20 side-chain, which is triggered by the formation of the complex. Conformational changes between unbound Ugi and Ugi complexed with UDG involve the beta-zipper structural motif, which we have named for the reversible pairing observed between intramolecular beta-strands. A similar beta-zipper is observed in the conversion between the open and closed forms of UDG. The combination of extremely high levels of pre-existing structural complementarity to DNA binding features specific to UDG with key local conformational changes in Ugi resolves the UDG-Ugi paradox and suggests a potentially general structural solution to the formation of very high affinity DNA enzyme-inhibitor complexes that avoid cross- reactivity.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Mar
pubmed:issn
0022-2836
pubmed:author
pubmed:copyrightInfo
Copyright 1999 Academic Press.
pubmed:issnType
Print
pubmed:day
26
pubmed:volume
287
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
331-46
pubmed:dateRevised
2007-11-14
pubmed:meshHeading
pubmed-meshheading:10080896-Amino Acid Sequence, pubmed-meshheading:10080896-Binding Sites, pubmed-meshheading:10080896-Crystallography, X-Ray, pubmed-meshheading:10080896-DNA Glycosylases, pubmed-meshheading:10080896-DNA-Binding Proteins, pubmed-meshheading:10080896-Enzyme Inhibitors, pubmed-meshheading:10080896-Escherichia coli, pubmed-meshheading:10080896-Hydrogen Bonding, pubmed-meshheading:10080896-Models, Molecular, pubmed-meshheading:10080896-Molecular Sequence Data, pubmed-meshheading:10080896-Mutation, pubmed-meshheading:10080896-N-Glycosyl Hydrolases, pubmed-meshheading:10080896-Nucleic Acid Conformation, pubmed-meshheading:10080896-Protein Binding, pubmed-meshheading:10080896-Protein Conformation, pubmed-meshheading:10080896-Protein Structure, Secondary, pubmed-meshheading:10080896-Sequence Alignment, pubmed-meshheading:10080896-Uracil-DNA Glycosidase, pubmed-meshheading:10080896-Viral Proteins
pubmed:year
1999
pubmed:articleTitle
Protein mimicry of DNA from crystal structures of the uracil-DNA glycosylase inhibitor protein and its complex with Escherichia coli uracil-DNA glycosylase.
pubmed:affiliation
Department of Molecular Biology, Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA, 92037, USA.
pubmed:publicationType
Journal Article, Research Support, U.S. Gov't, P.H.S., Research Support, U.S. Gov't, Non-P.H.S., Research Support, Non-U.S. Gov't