Scripps VIVO scripps research logo

  • Index
  • Log in
  • Home
  • People
  • Organizations
  • Research
  • Events
Search form

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

Academic Article
uri icon
  • Overview
  • Identity
  • Additional Document Info
  • View All
scroll to property group menus

Overview

authors

  • Tiefenbrunn Sample, Theresa
  • Forli, Stefano
  • Baksh, M. M.
  • Chang, M. W.
  • Happer, M.
  • Lin, Y. C.
  • Perryman, A. L.
  • Rhee, J. K.
  • Torbett, Bruce
  • Olson, Arthur
  • Elder, John
  • Finn, M.G.
  • Stout, C. David

publication date

  • 2013

journal

  • ACS Chemical Biology  Journal

abstract

  • 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.

subject areas

  • Crystallography, X-Ray
  • HIV Infections
  • HIV Protease
  • HIV Protease Inhibitors
  • HIV-1
  • Humans
  • Indoles
  • Molecular Docking Simulation
  • Pepstatins
  • Propionates
  • Protein Conformation
scroll to property group menus

Identity

PubMed Central ID

  • PMC3769432

International Standard Serial Number (ISSN)

  • 1554-8937 (Electronic) 1554-8929 (Linking)

Digital Object Identifier (DOI)

  • 10.1021/cb300611p

PubMed ID

  • 23540839
scroll to property group menus

Additional Document Info

start page

  • 1223

end page

  • 1231

©2019 The Scripps Research Institute | Terms of Use | Powered by VIVO

  • About
  • Contact Us
  • Support