期刊
ACS CHEMICAL BIOLOGY
卷 9, 期 3, 页码 743-751出版社
AMER CHEMICAL SOC
DOI: 10.1021/cb400791u
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资金
- Wellcome Trust University [085176/Z/08/Z]
- Darwin Trust PhD studentship
- BBSRC [BB/J000884/1]
- BBSRC [BB/J000884/1] Funding Source: UKRI
- Wellcome Trust [085176/Z/08/Z] Funding Source: Wellcome Trust
- Biotechnology and Biological Sciences Research Council [BB/J000884/1] Funding Source: researchfish
DNA transposases catalyze the movement of transposons around genomes by a cut-and-paste mechanism related to retroviral integration. Transposases and retroviral integrases share a common RNaseH-like domain with a catalytic DDE/D triad that coordinates the divalent cations required for DNA cleavage and integration. The anti-retroviral drugs Raltegravir and Elvitegravir inhibit integrases by displacing viral DNA ends from the catalytic metal ions. We demonstrate that Raltegravir, but not Elvitegravir, binds to Mos1 transposase in the presence of Mg2+ or Mn2+, without the requirement for transposon DNA, and inhibits transposon cleavage and DNA integration in biochemical assays. Crystal structures at 1.7 angstrom resolution show Raltegravir, in common with integrases, coordinating two Mg2+ or Mn2+ ions in the Mos1 active site. However, in the absence of transposon ends, the drug adopts an unusual, compact binding mode distinct from that observed in the active site of the prototype foamy virus integrase.
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