5FPT

Structure of hepatitis C virus (HCV) full-length NS3 complex with small-molecule ligand 2-(1-methyl-1H-indol-3-yl)acetic acid (AT3437) in an alternate binding site.

Summary for 5FPT

• Entry DOI: 10.2210/pdb5fpt/pdb
• Related: 5FP5 5FP6 5FPD 5FPE 5FPM 5FPN 5FPO 5FPR 5FPS 5FPY
• Descriptor: HEPATITIS C VIRUS FULL-LENGTH NS3 COMPLEX, (1-methyl-1H-indol-3-yl)acetic acid (3 entities in total)
• Functional Keywords: hepatitis c virus, hcv, ns3 complex, protease-helicase, hydrolase, protein-ligand complex, fragment screening, alternate binding site, at3437.
• Biological source: HEPATITIS C VIRUS (ISOLATE BK)
• Cellular location: Core protein p21: Host endoplasmic reticulum membrane; Single-pass membrane protein. Core protein p19: Virion . Envelope glycoprotein E1: Virion membrane ; Single-pass type I membrane protein . Envelope glycoprotein E2: Virion membrane ; Single-pass type I membrane protein . p7: Host endoplasmic reticulum membrane ; Multi-pass membrane protein . Protease NS2-3: Host endoplasmic reticulum membrane ; Multi-pass membrane protein . Serine protease NS3: Host endoplasmic reticulum membrane ; Peripheral membrane protein . Non-structural protein 4A: Host endoplasmic reticulum membrane ; Single-pass type I membrane protein . Non-structural protein 4B: Host endoplasmic reticulum membrane ; Multi-pass membrane protein . Non-structural protein 5A: Host endoplasmic reticulum membrane ; Peripheral membrane protein . RNA-directed RNA polymerase: Host endoplasmic reticulum membrane ; Single-pass type I membrane protein : P26663
• Total number of polymer chains: 2
• Total formula weight: 142117.20

Authors

Jhoti, H.,Ludlow, R.F.,Saini, H.K.,Tickle, I.J.,Verdonk, M.,Pathuri, P.,Williams, P.A. (deposition date: 2015-12-02, release date: 2015-12-23, Last modification date: 2024-01-10)

Primary citation

Ludlow, R.F.,Verdonk, M.L.,Saini, H.K.,Tickle, I.J.,Jhoti, H.
Detection of Secondary Binding Sites in Proteins Using Fragment Screening.
Proc.Natl.Acad.Sci.USA, 112:15910-, 2015

PubMed 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.

PubMed: 26655740
DOI: 10.1073/PNAS.1518946112

Experimental method

X-RAY DIFFRACTION (2.72 Å)