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Literature DB >> 7583655

A plasmid-encoded dihydrofolate reductase from trimethoprim-resistant bacteria has a novel D2-symmetric active site.

N Narayana¹, D A Matthews, E E Howell, X Nguyen-huu.

Abstract

Bacteria expressing R67-plasmid encoded dihydrofolate reductase (R67 DHFR) exhibit high-level resistance to the antibiotic trimethoprim. Native R67 DHFR is a 34,000 M(r) homotetramer which exists in equilibrium with an inactive dimeric form. The structure of native R67 DHFR has now been solved at 1.7 A resolution and is unrelated to that of chromosomal DHFR. Homotetrameric R67 DHFR has an unusual pore, 25 A in length, passing through the middle of the molecule. Two folate molecules bind asymmetrically within the pore indicating that the enzyme's active site consists of symmetry related binding surfaces from all four identical units.

Entities: Chemical Gene

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Year: 1995 PMID： 7583655 DOI： 10.1038/nsb1195-1018

Source DB: PubMed Journal: Nat Struct Biol ISSN： 1072-8368

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Cited

22 in total

1. One site fits both: a model for the ternary complex of folate + NADPH in R67 dihydrofolate reductase, a D2 symmetric enzyme.

Authors: E E Howell; U Shukla; S N Hicks; R D Smiley; L A Kuhn; M I Zavodszky
Journal: J Comput Aided Mol Des Date: 2001-11 Impact factor: 3.686

2. Refinement of homology-based protein structures by molecular dynamics simulation techniques.

Authors: Hao Fan; Alan E Mark
Journal: Protein Sci Date: 2004-01 Impact factor: 6.725

3. Effect of multiple symmetries on the association of R67 DHFR subunits bearing interfacial complementing mutations.

Authors: Julie Dam; Arnaud Blondel
Journal: Protein Sci Date: 2004-01 Impact factor: 6.725

4. Dramatic acceleration of protein folding by stabilization of a nonnative backbone conformation.

Authors: Ariel A Di Nardo; Dmitry M Korzhnev; Peter J Stogios; Arash Zarrine-Afsar; Lewis E Kay; Alan R Davidson
Journal: Proc Natl Acad Sci U S A Date: 2004-05-17 Impact factor: 11.205

5. Multiple ligand-binding modes in bacterial R67 dihydrofolate reductase.

Authors: Hernán Alonso; Malcolm B Gillies; Peter L Cummins; Andrey A Bliznyuk; Jill E Gready
Journal: J Comput Aided Mol Des Date: 2005-03 Impact factor: 3.686

6. Asymmetric mutations in the tetrameric R67 dihydrofolate reductase reveal high tolerance to active-site substitutions.

Authors: Maximilian C C J C Ebert; Krista L Morley; Jordan P Volpato; Andreea R Schmitzer; Joelle N Pelletier
Journal: Protein Sci Date: 2014-12-26 Impact factor: 6.725

A plasmid-encoded dihydrofolate reductase from trimethoprim-resistant bacteria has a novel D2-symmetric active site.

1. One site fits both: a model for the ternary complex of folate + NADPH in R67 dihydrofolate reductase, a D2 symmetric enzyme.

2. Refinement of homology-based protein structures by molecular dynamics simulation techniques.

3. Effect of multiple symmetries on the association of R67 DHFR subunits bearing interfacial complementing mutations.

4. Dramatic acceleration of protein folding by stabilization of a nonnative backbone conformation.

5. Multiple ligand-binding modes in bacterial R67 dihydrofolate reductase.

6. Asymmetric mutations in the tetrameric R67 dihydrofolate reductase reveal high tolerance to active-site substitutions.

7. Novel crystallization conditions for tandem variant R67 DHFR yield a wild-type crystal structure.

8. In Vivo Titration of Folate Pathway Enzymes.

9. Structure of the Q67H mutant of R67 dihydrofolate reductase-NADP+ complex reveals a novel cofactor binding mode.

10. Identification and energetic ranking of possible docking sites for pterin on dihydrofolate reductase.