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1.
J Med Chem ; 55(23): 10786-90, 2012 Dec 13.
Artigo em Inglês | MEDLINE | ID: mdl-23145792

RESUMO

An efficient way to rapidly generate protein-ligand costructures based on solution-NMR using sparse NOE data combined with selective isotope labeling is presented. A docked model of the 27 kDa N-terminal ATPase domain of Hsp90 bound to a small molecule ligand was generated using only 21 intermolecular NOEs, which uniquely defined both the binding site and the orientation of the ligand. The approach can prove valuable for the early stages of fragment-based drug discovery.


Assuntos
Ressonância Magnética Nuclear Biomolecular/métodos , Proteínas/química , Adenosina Trifosfatases/metabolismo , Proteínas de Choque Térmico HSP90/metabolismo , Ligantes
2.
DNA Repair (Amst) ; 10(9): 915-25, 2011 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-21752727

RESUMO

Rev1 is a eukaryotic DNA polymerase of the Y family involved in translesion synthesis (TLS), a major damage tolerance pathway that allows DNA replication at damaged templates. Uniquely amongst the Y family polymerases, the N-terminal part of Rev1, dubbed the BRCA1 C-terminal homology (BRCT) region, includes a BRCT domain. While most BRCT domains mediate protein-protein interactions, Rev1 contains a predicted α-helix N-terminal to the BRCT domain and in human Replication Factor C (RFC) such a BRCT region endows the protein with DNA binding capacity. Here, we studied the DNA binding properties of yeast and mouse Rev1. Our results show that the BRCT region of Rev1 specifically binds to a 5' phosphorylated, recessed, primer-template junction. This DNA binding depends on the extra α-helix, N-terminal to the BRCT domain. Surprisingly, a stretch of 20 amino acids N-terminal to the predicted α-helix is also critical for high-affinity DNA binding. In addition to 5' primer-template junction binding, Rev1 efficiently binds to a recessed 3' primer-template junction. These dual DNA binding characteristics are discussed in view of the proposed recruitment of Rev1 by 5' primer-template junctions, downstream of stalled replication forks.


Assuntos
DNA Polimerase Dirigida por DNA/metabolismo , DNA/metabolismo , Nucleotidiltransferases/metabolismo , Proteínas de Saccharomyces cerevisiae/metabolismo , Motivos de Aminoácidos , Sequência de Aminoácidos , Animais , DNA/genética , Vetores Genéticos/genética , Camundongos , Dados de Sequência Molecular , Nucleotidiltransferases/genética , Nucleotidiltransferases/isolamento & purificação , Proteínas de Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/isolamento & purificação , Alinhamento de Sequência
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