4EJ8: Apo HIV Protease (PR) dimer in closed form with fragment 1F1 in the outside/top of flap

Citation:
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 degrees 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.
PDB ID: 4EJ8Download
MMDB ID: 109554
PDB Deposition Date: 2012/4/6
Updated in MMDB: 2013/05
Experimental Method:
x-ray diffraction
Resolution: 2.347  Å
Source Organism:
Similar Structures:
Biological Unit for 4EJ8: dimeric; determined by author and by software (PISA)
Molecular Components in 4EJ8
Label Count Molecule
Proteins (2 molecules)
2
Protease
Molecule annotation
Chemicals (10 molecules)
1
5
2
4
3
1
* Click molecule labels to explore molecular sequence information.

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