AI Article Synopsis
- The fragment indole-6-carboxylic acid (1F1) and another fragment, 3-indolepropionic acid (1F1-N), have been shown to bind to the HIV protease (PR), specifically at the flap site, which is crucial for the enzyme's function.
- Both fragments were co-crystallized with different forms of PR and demonstrated the ability to stabilize the apo-PR by increasing its melting temperature (Tm) by 3.5-5 °C.
- Furthermore, the binding studies revealed that 1F1 and 1F1-N exhibit strong binding affinities to both the closed form of apo-PR and the pepstatin-inhibited PR, with a greater
Article 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.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3769432 | PMC |
| http://dx.doi.org/10.1021/cb300611p | DOI Listing |
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