Structural basis for retroviral intasome assembly and integrase inhibitor action

Authors: Peter Cherepanov (Imperial College London)
Co-authored by industrial partner: No

Type: Magazine Article
Magazine: Science

State: Published (Approved)
Published: October 2010

Abstract: To establish successful infection, a retrovirus must insert DNA replica of its genome into a host cell chromosome. This process is catalysed by integrase (IN), the viral enzyme that synapses ends of viral DNA forming a highly stable nucleoprotein complex, intasome. The structure of full-length IN, either separately or in complex with viral DNA, has been lacking. Furthermore, although clinically useful inhibitors of HIV IN have been developed, their mechanism of action remained speculative. Using data acquired at Diamond beamlines I02 and I04, we determined the long-sought-after crystal structure of a functional retroviral intasome, revealing a tetramer of IN assembled on viral DNA ends. Soaking intasome crystals in the presence of clinical HIV IN inhibitors Raltegravir and Elvitegravir elucidated their common mechanism of action. Binding within the active site, the drugs cause dislocation of the reactive 3’ viral DNA end, disarming the viral nucleoprotein complex. These results represent a quantum leap in understanding of the retroviral DNA integration process and provide a platform for rational design of IN inhibitors.

Journal Keywords: Retrovirus; Integrase; Viral enzyme

Subject Areas: Biology and Bio-materials, Technique Development, Medicine

Instruments: I02-Macromolecular Crystallography , I04-Macromolecular Crystallography

Added On: 08/08/2016 15:44

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