Structural and Biochemical Analysis of Sliding Clamp/Ligand Interactions Suggest a Competition Between Replicative and Translesion DNA Polymerases

Burnouf, Dominique; Oliéric, V.; Wagner, Jérôme; Fujii, Shingo; Reinbolt, Joseph; Fuchs, Robert P. P.; Dumas, Philippe

doi:10.1016/j.jmb.2003.11.049

Cited by 101 publications

(162 citation statements)

References 53 publications

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“…S5), as noted (10). Moreover, the structure of the S. pyogenes ␤-clamp has been solved (PDB ID code 2AVT) (20), and superposition of residues that form the protein-binding pocket of the Gram-negative E. coli ␤-clamp and the ␤-clamp of the Gram-positive S. pyogenes bacterium, results in only minor differences between corresponding ␣-carbon atoms (i.e., up to 0.36 Å) (Fig.…”

Section: Identification Of a Small-molecule Compound That Binds The Pmentioning

confidence: 67%

“…The Pol II peptide makes unique contacts to residues His 175 and Val 361 in subsite 1, which do not appear to contact RU7 or the Pol III 9-mer. Superposition of the Pol IV peptide, which was solved in an earlier study (10), with the Pol II and Pol III peptides show that the Pol IV peptide binds to subsite 2, similar to Pols II and III, but the Pol IV peptide binds to subsite 1 of ␤ in yet a different way than either Pol II or Pol III (Fig. 5B).…”

Section: Identification Of a Small-molecule Compound That Binds The Pmentioning

confidence: 77%

“…The peptide-binding pocket of sliding clamps is located between two domains on each protomer (8,10). The binding pocket of the bacterial ␤-clamp is located between domains II and III, as demonstrated by structures of ␤ bound to the ␦-clamp loading subunit (11) and the ␤-Pol IV complex (10,12).…”

Section: S/d]lf and Qlxlx[l/f] (9)mentioning

confidence: 99%

“…The binding pocket of the bacterial ␤-clamp is located between domains II and III, as demonstrated by structures of ␤ bound to the ␦-clamp loading subunit (11) and the ␤-Pol IV complex (10,12). The proteinbinding pocket of ␤ consists of two subsites (10).…”

Section: S/d]lf and Qlxlx[l/f] (9)mentioning

confidence: 99%

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Structure of a small-molecule inhibitor of a DNA polymerase sliding clamp

Georgescu

Yurieva

Kim

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

154

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DNA polymerases attach to the DNA sliding clamp through a common overlapping binding site. We identify a small-molecule compound that binds the protein-binding site in the Escherichia coli ␤-clamp and differentially affects the activity of DNA polymerases II, III, and IV. To understand the molecular basis of this discrimination, the cocrystal structure of the chemical inhibitor is solved in complex with ␤ and is compared with the structures of Pol II, Pol III, and Pol IV peptides bound to ␤. The analysis reveals that the small molecule localizes in a region of the clamp to which the DNA polymerases attach in different ways. The results suggest that the small molecule may be useful in the future to probe polymerase function with ␤, and that the ␤-clamp may represent an antibiotic target.antibiotic target ͉ rational drug design ͉ fluorescence anisotropy ͉ crystallography T he replication machinery of all cells utilizes a ring-shaped, sliding-clamp protein that encircles DNA and slides along the duplex, thus acting as a mobile tether to hold the chromosomal replicase to DNA for high processivity (1-3). Sliding clamps from the three domains of life are remarkably similar in architecture (4-6). They consist of six domains of similar chain fold. The bacterial ␤-clamp is a homodimer, and each protomer consists of three domains, whereas eukaryotic and archaeal proliferating cell nuclear antigen (PCNA) clamps are homotrimers formed from protomers containing two domains each.Initially, ␤ and PCNA were identified as processivity factors for chromosomal replicases, but sliding clamps are now known to function with diverse DNA polymerases, repair factors, and cell cycle-control proteins (reviewed in ref.

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Section: Identification Of a Small-molecule Compound That Binds The Pmentioning

confidence: 67%

Section: Identification Of a Small-molecule Compound That Binds The Pmentioning

confidence: 77%

Section: S/d]lf and Qlxlx[l/f] (9)mentioning

confidence: 99%

Section: S/d]lf and Qlxlx[l/f] (9)mentioning

confidence: 99%

See 2 more Smart Citations

Structure of a small-molecule inhibitor of a DNA polymerase sliding clamp

Georgescu

Yurieva

Kim

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

154

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“…Mutagenesis of the proposed b 2 -binding sites of the repair polymerases Pol II, Pol IV and Pol V ablated translesion synthesis in vivo (27). Recent structures of fragments of Pol IV, containing a hexameric b 2 -binding motif revealed that two leucines are involved in similar interactions with the b-binding surface as the L 73 F 74 of the d subunit (28,29). Thus, all three types of b-binding motif (from d, pentapeptide and hexapeptide) have a conserved core of interaction at the same site on b 2 .…”

Section: The B 2 Sliding Clamp Is Used By Many Dna Polymerases and Dnmentioning

confidence: 99%

Conservation of Eubacterial Replicases

Wijffels

Dalrymple

Kongsuwan

et al. 2005

IUBMB Life (International Union of Biochemistry and Molecular B

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SummaryThe last 15 years of effort in understanding bacterial DNA replication and repair has identified that the donut shaped b 2 sliding clamp is harnessed by very functionally different DNA polymerases throughout the lifecycle of the bacterial cell. Remarkably, the sites of binding of these polymerases, in most cases, appear to be the same shallow pocket on the b dimer. In every case, binding of b 2 by the polymerase enhances their processivity of DNA synthesis. This binding site is also the same point of interaction between b 2 and the clamp loader complex, which binds b 2 , opens and places it onto the DNA strand and then vacates the site. b 2 may also be involved in the initiation of DNA replication again via contact through this same site. While much of the research effort has focused on Escherichia coli and Bacillus subtilis, conservation of this complex system is becoming apparent in diverse bacteria. IUBMB Life, 57: 413 -419, 2005

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Repair and Mutagenesis of DNA

Devoret

2006

Encyclopedia of Molecular Cell Biology and Molecular Medicine

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Structural and Biochemical Analysis of Sliding Clamp/Ligand Interactions Suggest a Competition Between Replicative and Translesion DNA Polymerases

Cited by 101 publications

References 53 publications

Structure of a small-molecule inhibitor of a DNA polymerase sliding clamp

Structure of a small-molecule inhibitor of a DNA polymerase sliding clamp

Conservation of Eubacterial Replicases

Repair and Mutagenesis of DNA

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