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Small Molecule Regulation of Protein Conformation by Binding in the Flap of HIV Protease

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† †Deparatment 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
*(T.T.) Phone: 858-784-2110. Fax: 858-784-2857. E-mail: [email protected]
Cite this: ACS Chem. Biol. 2013, 8, 6, 1223–1231
Publication Date (Web):March 29, 2013
https://doi.org/10.1021/cb300611p
Copyright © 2013 American Chemical Society
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    Abstract

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    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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    Refinement statistics, chemical structures, rmsd comparisons, AutoDock binding modes, FRET-based inhibition results, electron density. This material is available free of charge via the Internet at http://pubs.acs.org.

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    Coordinates and structure factors have been deposited in the Protein Data Bank with accession numbers 4EJ8, 4EJD, 4EJK, and 4EJL.

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    Most electronic Supporting Information files are available without a subscription to ACS Web Editions. Such files may be downloaded by article for research use (if there is a public use license linked to the relevant article, that license may permit other uses). Permission may be obtained from ACS for other uses through requests via the RightsLink permission system: http://pubs.acs.org/page/copyright/permissions.html.

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