5FPY: Structure Of Hepatitis C Virus (hcv) Full-length Ns3 Complex With Small-molecule Ligand 5-bromo-1-methyl-1h-indole-2- Carboxylic Acid (at21457) In An Alternate Binding Site

Citation:
Abstract
Proteins need to be tightly regulated as they control biological processes in most normal cellular functions. The precise mechanisms of regulation are rarely completely understood but can involve binding of endogenous ligands and/or partner proteins at specific locations on a protein that can modulate function. Often, these additional secondary binding sites appear separate to the primary binding site, which, for example for an enzyme, may bind a substrate. In previous work, we have uncovered several examples in which secondary binding sites were discovered on proteins using fragment screening approaches. In each case, we were able to establish that the newly identified secondary binding site was biologically relevant as it was able to modulate function by the binding of a small molecule. In this study, we investigate how often secondary binding sites are located on proteins by analyzing 24 protein targets for which we have performed a fragment screen using X-ray crystallography. Our analysis shows that, surprisingly, the majority of proteins contain secondary binding sites based on their ability to bind fragments. Furthermore, sequence analysis of these previously unknown sites indicate high conservation, which suggests that they may have a biological function, perhaps via an allosteric mechanism. Comparing the physicochemical properties of the secondary sites with known primary ligand binding sites also shows broad similarities indicating that many of the secondary sites may be druggable in nature with small molecules that could provide new opportunities to modulate potential therapeutic targets.
PDB ID: 5FPYDownload
MMDB ID: 135112
PDB Deposition Date: 2015/12/3
Updated in MMDB: 2015/12
Experimental Method:
x-ray diffraction
Resolution: 2.52  Å
Source Organism:
Similar Structures:
Biological Unit for 5FPY: dimeric; determined by author and by software (PISA)
Molecular Components in 5FPY
Label Count Molecule
Proteins (2 molecules)
2
Serine Protease NS3
Molecule annotation
Chemicals (2 molecules)
1
2
* Click molecule labels to explore molecular sequence information.

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