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Instruments / Technical Area	Publication Details	Published	Actions
I04-1-Macromolecular Crystallography (fixed wavelength)	Sliding of HIV-1 reverse transcriptase over DNA creates a transient P pocket – targeting P-pocket by fragment screening Abhimanyu Singh , Sergio E. Martinez , Weijie Gu , Hoai Nguyen , Dominique Schols , Piet Herdewijn , Steven De Jonghe , Kalyan Das Nature Communications 12 DOI: 10.1038/s41467-021-27409-y Diamond Proposal Number(s): [22010] Open Access Show Abstract ▼ Abstract: HIV-1 reverse transcriptase (RT) slides over an RNA/DNA or dsDNA substrate while copying the viral RNA to a proviral DNA. We report a crystal structure of RT/dsDNA complex in which RT overstepped the primer 3’-end of a dsDNA substrate and created a transient P-pocket at the priming site. We performed a high-throughput screening of 300 drug-like fragments by X-ray crystallography that identifies two leads that bind the P-pocket, which is composed of structural elements from polymerase active site, primer grip, and template-primer that are resilient to drug-resistance mutations. Analogs of a fragment were synthesized, two of which show noticeable RT inhibition. An engineered RT/DNA aptamer complex could trap the transient P-pocket in solution, and structures of the RT/DNA complex were determined in the presence of an inhibitory fragment. A synthesized analog bound at P-pocket is further analyzed by single-particle cryo-EM. Identification of the P-pocket within HIV RT and the developed structure-based platform provide an opportunity for the design new types of polymerase inhibitors.	Dec 2021

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I04-1-Macromolecular Crystallography (fixed wavelength)

Sliding of HIV-1 reverse transcriptase over DNA creates a transient P pocket – targeting P-pocket by fragment screening

Abhimanyu Singh , Sergio E. Martinez , Weijie Gu , Hoai Nguyen , Dominique Schols , Piet Herdewijn , Steven De Jonghe , Kalyan Das

Nature Communications 12

DOI: 10.1038/s41467-021-27409-y

Diamond Proposal Number(s): [22010]