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ACS Chem Biol. 2013;8(6):1223-31. doi: 10.1021/cb300611p. Epub 2013 Mar 29.

Small molecule regulation of protein conformation by binding in the Flap of HIV protease.

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  • 1Deparatment of Integrative Structural and Computational Biology, ‡Department of Chemistry, §Department of Molecular and Experimental Medicine, ∥Department of Immunology and Microbial Science, The Scripps Research Institute , 10550 N. Torrey Pines Rd., La Jolla, California 92037, United States.


The fragment indole-6-carboxylic acid (1F1), previously identified as a flap site binder in a fragment-based screen against HIV protease (PR), has been cocrystallized with pepstatin-inhibited PR and with apo-PR. Another fragment, 3-indolepropionic acid (1F1-N), predicted by AutoDock calculations and confirmed in a novel inhibition of nucleation crystallization assay, exploits the same interactions in the flap site in two crystal structures. Both 1F1 and 1F1-N bind to the closed form of apo-PR and to pepstatin:PR. In solution, 1F1 and 1F1-N raise the Tm of apo-PR by 3.5-5 °C as assayed by differential scanning fluorimetry (DSF) and show equivalent low-micromolar binding constants to both apo-PR and pepstatin:PR, assayed by backscattering interferometry (BSI). The observed signal intensities in BSI are greater for each fragment upon binding to apo-PR than to pepstatin-bound PR, consistent with greater conformational change in the former binding event. Together, these data indicate that fragment binding in the flap site favors a closed conformation of HIV PR.

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