Faculty Opinions recommendation of Crystal structure of a novel conformational state of the flavivirus NS3 protein: implications for polyprotein processing and viral replication.

2009 ◽  
Author(s):  
Patricia C Weber
Keyword(s):  
Crystal Structure ◽  
Viral Replication ◽  
Conformational State ◽  
Polyprotein Processing ◽  
Ns3 Protein

Structure Based Identification of Potential Inhibitors of NS3 Protein of Zika Virus

2019 ◽  
Vol 16 (7) ◽  
pp. 761-774
Author(s):  
Md. Imam Faizan ◽  
Abu Turab Naqvi ◽  
Md. Imtaiyaz Hassan ◽  
Mohd. Abdullah ◽  
Ayesha Tazeen ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Zika Virus ◽  
Genome Replication ◽  
Ns3 Protein ◽  
Computational Data ◽  
Drug Designing ◽  
Therapeutic Molecules ◽  
Future Drug ◽  
Approved Drugs ◽  
Potential Inhibitors

Background:The re-emerging Zika virus has posed a serious threat to human health due to its association with the neurological disorders. The NS3 protein of Zika virus plays a pivotal role in the genome replication and thus may prove to be a critical target for the drug designing studies.Objective:The present study was conceptualized to analyze the crystal structure of NS3 protein of Zika virus followed by the identification of it’s potential inhibitors.Methods:Crystal structure of the NS3 protein was evaluated in detail. Docking of the NS3 protein was done with 130 different ligands including dengue virus inhibitors and their similar compounds along with some approved drugs. The drug likeliness properties were checked for non drug compounds.Results:Structural analysis of the NS3 protein revealed three important sites namely ATP- and RNAbinding sites as well as a central cavity. The selected ten ligands (ZINC05487635, ZINC0092398, ZINC13345444, 4-methoxyphenyl 4-chloro-3-nitrobenzoate, Luteolin, Ivermectin, Suramin, Dasatinib, Panduratin A, and ARDP0009) showed a higher binding affinity for the NS3 protein and good drug likeliness properties.Conclusion:These inhibitors could possibly act as potential lead molecules for future drug designing studies. Our present computational data is envisaged to be useful for gathering experimental evidences towards the development of potential therapeutic molecules against this arthropod mediated pathogen.

scholarly journals Crystal Structure of Poliovirus 3CD Protein: Virally Encoded Protease and Precursor to the RNA-Dependent RNA Polymerase

2007 ◽  
Vol 81 (7) ◽  
pp. 3583-3596 ◽  
Author(s):  
Laura L. Marcotte ◽  
Amanda B. Wass ◽  
David W. Gohara ◽  
Harsh B. Pathak ◽  
Jamie J. Arnold ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Viral Replication ◽  
Active Site ◽  
Polymerase Activity ◽  
Rna Dependent Rna Polymerase ◽  
Multifunctional Protein ◽  
Biologically Relevant ◽  
N Terminus ◽  
Key Residues

ABSTRACT Poliovirus 3CD is a multifunctional protein that serves as a precursor to the protease 3Cpro and the viral polymerase 3Dpol and also plays a role in the control of viral replication. Although 3CD is a fully functional protease, it lacks polymerase activity. We have solved the crystal structures of 3CD at a 3.4-Å resolution and the G64S fidelity mutant of 3Dpol at a 3.0-Å resolution. In the 3CD structure, the 3C and 3D domains are joined by a poorly ordered polypeptide linker, possibly to facilitate its cleavage, in an arrangement that precludes intramolecular proteolysis. The polymerase active site is intact in both the 3CD and the 3Dpol G64S structures, despite the disruption of a network proposed to position key residues in the active site. Therefore, changes in molecular flexibility may be responsible for the differences in fidelity and polymerase activities. Extensive packing contacts between symmetry-related 3CD molecules and the approach of the 3C domain's N terminus to the VPg binding site suggest how 3Dpol makes biologically relevant interactions with the 3C, 3CD, and 3BCD proteins that control the uridylylation of VPg during the initiation of viral replication. Indeed, mutations designed to disrupt these interfaces have pronounced effects on the uridylylation reaction in vitro.

scholarly journals The C-terminal 50 Amino Acid Residues of Dengue NS3 Protein Are Important for NS3-NS5 Interaction and Viral Replication

2014 ◽  
Vol 290 (4) ◽  
pp. 2379-2394 ◽  
Author(s):  
Moon Y. F. Tay ◽  
Wuan Geok Saw ◽  
Yongqian Zhao ◽  
Kitti W. K. Chan ◽  
Daljit Singh ◽  
...  
Keyword(s):  
Amino Acid ◽  
Viral Replication ◽  
Amino Acid Residues ◽  
Ns3 Protein

scholarly journals Molecular views of viral polyprotein processing revealed by the crystal structure of the hepatitis C virus bifunctional protease–helicase

Structure ◽  
1999 ◽  
Vol 7 (11) ◽  
pp. 1353-1363 ◽  
Author(s):  
Nanhua Yao ◽  
Paul Reichert ◽  
S Shane Taremi ◽  
Winifred W Prosise ◽  
Patricia C Weber
Keyword(s):  
Crystal Structure ◽  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Polyprotein Processing ◽  
Viral Polyprotein

scholarly journals Zinc2+ ion inhibits SARS-CoV-2 main protease and viral replication in vitro.

2021 ◽  
Author(s):  
Love Panchariya ◽  
Wajahat Ali Khan ◽  
Shobhan Kuila ◽  
Kirtishila Sonkar ◽  
Sibasis Sahoo ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Clinical Trials ◽  
Clinical Outcome ◽  
Viral Replication ◽  
Zinc Deficiency ◽  
Poor Prognosis ◽  
Molecular Target ◽  
Structural Basis ◽  
Main Protease

Zinc deficiency is linked to poor prognosis in COVID-19 patients while clinical trials with Zinc demonstrate better clinical outcome. The molecular target and mechanistic details of anti-coronaviral (SARS-CoV2) activity of Zinc remain obscure. We show that ionic Zinc not only inhibits SARS-CoV-2 main protease (Mpro) with nanomolar affinity, but also viral replication. We present the first crystal structure of Mpro-Zinc2+ complex at 1.9 Å and provide the structural basis of viral replication inhibition.

scholarly journals Susceptibility of β1 Na+-K+ Pump Subunit to Glutathionylation and Oxidative Inhibition Depends on Conformational State of Pump

2012 ◽  
Vol 287 (15) ◽  
pp. 12353-12364 ◽  
Author(s):  
Chia-Chi Liu ◽  
Alvaro Garcia ◽  
Yasser A. Mahmmoud ◽  
Elisha J. Hamilton ◽  
Keyvan Karimi Galougahi ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Membrane Potential ◽  
Angiotensin Ii ◽  
Conformational Changes ◽  
Ventricular Myocytes ◽  
Conformational State ◽  
Side Chain ◽  
Voltage Dependent ◽  
Cytosolic Glutathione ◽  
And Function

Glutathionylation of cysteine 46 of the β1 subunit of the Na+-K+ pump causes pump inhibition. However, the crystal structure, known in a state analogous to an E2·2K+·Pi configuration, indicates that the side chain of cysteine 46 is exposed to the lipid bulk phase of the membrane and not expected to be accessible to the cytosolic glutathione. We have examined whether glutathionylation depends on the conformational changes in the Na+-K+ pump cycle as described by the Albers-Post scheme. We measured β1 subunit glutathionylation and function of Na+-K+-ATPase in membrane fragments and in ventricular myocytes. Signals for glutathionylation in Na+-K+-ATPase-enriched membrane fragments suspended in solutions that preferentially induce E1ATP and E1Na3 conformations were much larger than signals in solutions that induce the E2 conformation. Ouabain further reduced glutathionylation in E2 and eliminated an increase seen with exposure to the oxidant peroxynitrite (ONOO−). Inhibition of Na+-K+-ATPase activity after exposure to ONOO− was greater when the enzyme had been in the E1Na3 than the E2 conformation. We exposed myocytes to different extracellular K+ concentrations to vary the membrane potential and hence voltage-dependent conformational poise. K+ concentrations expected to shift the poise toward E2 species reduced glutathionylation, and ouabain eliminated a ONOO−-induced increase. Angiotensin II-induced NADPH oxidase-dependent Na+-K+ pump inhibition was eliminated by conditions expected to shift the poise toward the E2 species. We conclude that susceptibility of the β1 subunit to glutathionylation depends on the conformational poise of the Na+-K+ pump.

scholarly journals Crystal Structure of a Novel Conformational State of the Flavivirus NS3 Protein: Implications for Polyprotein Processing and Viral Replication

2009 ◽  
Vol 83 (24) ◽  
pp. 12895-12906 ◽  
Author(s):  
René Assenberg ◽  
Eloise Mastrangelo ◽  
Thomas S. Walter ◽  
Anil Verma ◽  
Mario Milani ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Serine Protease ◽  
Biochemical Characterization ◽  
Nonstructural Protein ◽  
Structural Data ◽  
Murray Valley Encephalitis Virus ◽  
Ns3 Protein ◽  
Single Protein ◽  
Protease Activation

ABSTRACT The flavivirus genome comprises a single strand of positive-sense RNA, which is translated into a polyprotein and cleaved by a combination of viral and host proteases to yield functional proteins. One of these, nonstructural protein 3 (NS3), is an enzyme with both serine protease and NTPase/helicase activities. NS3 plays a central role in the flavivirus life cycle: the NS3 N-terminal serine protease together with its essential cofactor NS2B is involved in the processing of the polyprotein, whereas the NS3 C-terminal NTPase/helicase is responsible for ATP-dependent RNA strand separation during replication. An unresolved question remains regarding why NS3 appears to encode two apparently disconnected functionalities within one protein. Here we report the 2.75-Å-resolution crystal structure of full-length Murray Valley encephalitis virus NS3 fused with the protease activation peptide of NS2B. The biochemical characterization of this construct suggests that the protease has little influence on the helicase activity and vice versa. This finding is in agreement with the structural data, revealing a single protein with two essentially segregated globular domains. Comparison of the structure with that of dengue virus type 4 NS2B-NS3 reveals a relative orientation of the two domains that is radically different between the two structures. Our analysis suggests that the relative domain-domain orientation in NS3 is highly variable and dictated by a flexible interdomain linker. The possible implications of this conformational flexibility for the function of NS3 are discussed.

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