scholarly journals Insight into the HIV-1 Vif SOCS-box–ElonginBC interaction

Open Biology ◽  
2013 ◽  
Vol 3 (11) ◽  
pp. 130100 ◽  
Author(s):  
Zhisheng Lu ◽  
Julien R. C. Bergeron ◽  
R. Andrew Atkinson ◽  
Torsten Schaller ◽  
Dennis A. Veselkov ◽  
...  
Keyword(s):  
Solution Structure ◽  
Hydrophobic Interactions ◽  
Dynamic Information ◽  
Ubiquitin Ligase Complex ◽  
Biophysical Studies ◽  
Viral Infectivity Factor ◽  
Β Sheet ◽  
Socs Box ◽  
Insight Into ◽  
Hiv 1

The HIV-1 viral infectivity factor (Vif) neutralizes cell-encoded antiviral APOBEC3 proteins by recruiting a cellular ElonginB (EloB)/ElonginC (EloC)/Cullin5-containing ubiquitin ligase complex, resulting in APOBEC3 ubiquitination and proteolysis. The suppressors-of-cytokine-signalling-like domain (SOCS-box) of HIV-1 Vif is essential for E3 ligase engagement, and contains a BC box as well as an unusual proline-rich motif. Here, we report the NMR solution structure of the Vif SOCS–ElonginBC (EloBC) complex. In contrast to SOCS-boxes described in other proteins, the HIV-1 Vif SOCS-box contains only one α-helical domain followed by a β-sheet fold. The SOCS-box of Vif binds primarily to EloC by hydrophobic interactions. The functionally essential proline-rich motif mediates a direct but weak interaction with residues 101–104 of EloB, inducing a conformational change from an unstructured state to a structured state. The structure of the complex and biophysical studies provide detailed insight into the function of Vif's proline-rich motif and reveal novel dynamic information on the Vif–EloBC interaction.

scholarly journals MicroED structures of HIV-1 Gag CTD-SP1 reveal binding interactions with the maturation inhibitor bevirimat

2018 ◽  
Vol 115 (52) ◽  
pp. 13258-13263 ◽  
Author(s):  
Michael D. Purdy ◽  
Dan Shi ◽  
Jakub Chrustowicz ◽  
Johan Hattne ◽  
Tamir Gonen ◽  
...  
Keyword(s):  
Drug Discovery ◽  
Electrostatic Interactions ◽  
Hydrophobic Interactions ◽  
Binding Interactions ◽  
Structure Based Drug Design ◽  
Gag Polyprotein ◽  
Pentacyclic Triterpenoid ◽  
Maturation Inhibitor ◽  
Insight Into ◽  
Hiv 1

HIV-1 protease (PR) cleavage of the Gag polyprotein triggers the assembly of mature, infectious particles. Final cleavage of Gag occurs at the junction helix between the capsid protein CA and the SP1 spacer peptide. Here we used MicroED to delineate the binding interactions of the maturation inhibitor bevirimat (BVM) using very thin frozen-hydrated, 3D microcrystals of a CTD-SP1 Gag construct with and without bound BVM. The 2.9-Å MicroED structure revealed that a single BVM molecule stabilizes the six-helix bundle via both electrostatic interactions with the dimethylsuccinyl moiety and hydrophobic interactions with the pentacyclic triterpenoid ring. These results provide insight into the mechanism of action of BVM and related maturation inhibitors that will inform further drug discovery efforts. This study also demonstrates the capabilities of MicroED for structure-based drug design.

scholarly journals Human Lactoferricin Is Partially Folded in Aqueous Solution and Is Better Stabilized in a Membrane Mimetic Solvent

2005 ◽  
Vol 49 (8) ◽  
pp. 3387-3395 ◽  
Author(s):  
Howard N. Hunter ◽  
A. Ross Demcoe ◽  
Håvard Jenssen ◽  
Tore J. Gutteberg ◽  
Hans J. Vogel
Keyword(s):  
Aqueous Solution ◽  
Solution Structure ◽  
Hydrophobic Interactions ◽  
Peptide Bond ◽  
Intact Protein ◽  
Membrane Mimetic ◽  
Helical Content ◽  
Distinct Solution ◽  
Bovine Lactoferricin ◽  
Β Sheet

ABSTRACT Lactoferricins are highly basic bioactive peptides that are released in the stomach through proteolytic cleavage of various lactoferrin proteins. Here we have determined the solution structure of human lactoferricin (LfcinH) by conventional two-dimensional nuclear magnetic resonance methods in both aqueous solution and a membrane mimetic solvent. Unlike the 25-residue bovine lactoferricin (LfcinB), which adopts a somewhat distorted antiparallel β sheet, the longer LfcinH peptide shows a helical content from Gln14 to Lys29 in the membrane mimetic solvent but a nonexistent β-sheet character in either the N- or C-terminal regions of the peptide. The helical characteristic of the LfcinH peptide resembles the conformation that this region adopts in the crystal structure of the intact protein. The LfcinH structure determined in aqueous solution displays a nascent helix in the form of a coiled conformation in the region from Gln14 to Lys29. Numerous hydrophobic interactions create the basis for the better-defined overall structure observed in the membrane mimetic solvent. The 49-residue LfcinH peptide isolated for these studies was found to be slightly longer than previously reported peptide preparations and was found to have an intact peptide bond between residues Ala11 and Val12. The distinct solution structures of LfcinH and LfcinB represent a novel difference in the physical properties of these two peptides, which contributes to their unique physiological activities.

scholarly journals Solution Structure of the Conserved Hypothetical Protein Rv2302 from Mycobacterium tuberculosis

2006 ◽  
Vol 188 (16) ◽  
pp. 5993-6001 ◽  
Author(s):  
Garry W. Buchko ◽  
Chang-Yub Kim ◽  
Thomas C. Terwilliger ◽  
Michael A. Kennedy
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Solution Structure ◽  
Hydrophobic Interactions ◽  
Hypothetical Protein ◽  
Cd Spectroscopy ◽  
Size Exclusion ◽  
Correlation Spectrum ◽  
Nuclear Overhauser ◽  
Α Helix ◽  
Β Sheet

ABSTRACT The Mycobacterium tuberculosis protein Rv2302 (80 residues; molecular mass of 8.6 kDa) has been characterized using nuclear magnetic resonance (NMR) and circular dichroism (CD) spectroscopy. While the biochemical function of Rv2302 is still unknown, recent microarray analyses show that Rv2302 is upregulated in response to starvation and overexpression of heat shock proteins and, consequently, may play a role in the biochemical processes associated with these events. Rv2302 is a monomer in solution as shown by size exclusion chromatography and NMR spectroscopy. CD spectroscopy suggests that Rv2302 partially unfolds upon heating and that this unfolding is reversible. Using NMR-based methods, the solution structure of Rv2302 was determined. The protein contains a five-strand, antiparallel β-sheet core with one C-terminal α-helix (A61 to A75) nestled against its side. Hydrophobic interactions between residues in the α-helix and β-strands 3 and 4 hold the α-helix near the β-sheet core. The electrostatic potential on the solvent-accessible surface is primarily negative with the exception of a positive arginine pocket composed of residues R18, R70, and R74. Steady-state {1H}-15N heteronuclear nuclear Overhauser effects indicate that the protein's core is rigid on the picosecond timescale. The absence of amide cross-peaks for residues G13 to H19 in the 1H-15N heteronuclear single quantum correlation spectrum suggests that this region, a loop between β-strands 1 and 2, undergoes motion on the millisecond to microsecond timescale. Dali searches using the structure closest to the average structure do not identify any high similarities to any other known protein structure, suggesting that the structure of Rv2302 may represent a novel protein fold.

scholarly journals Structural Insight into the Mechanisms of Targeting and Signaling of Focal Adhesion Kinase

2002 ◽  
Vol 22 (8) ◽  
pp. 2751-2760 ◽  
Author(s):  
Gaohua Liu ◽  
Cristina D. Guibao ◽  
Jie Zheng
Keyword(s):  
Focal Adhesion Kinase ◽  
Focal Adhesion ◽  
Solution Structure ◽  
Hydrophobic Interactions ◽  
Focal Adhesions ◽  
Nonreceptor Tyrosine Kinase ◽  
Binding Partner ◽  
Focal Adhesion Turnover ◽  
Structural Insight ◽  
Insight Into

ABSTRACT Focal adhesion kinase (FAK) is a nonreceptor tyrosine kinase whose focal adhesion targeting (FAT) domain interacts with other focal adhesion molecules in integrin-mediated signaling. Localization of activated FAK to focal adhesions is indispensable for its function. Here we describe a solution structure of the FAT domain bound to a peptide derived from paxillin, a FAK-binding partner. The FAT domain is composed of four helices that form a “right-turn” elongated bundle; the globular fold is mainly maintained by hydrophobic interactions. The bound peptide further stabilizes the structure. Certain signaling events such as phosphorylation and molecule interplay may induce opening of the helix bundle. Such conformational change is proposed to precede departure of FAK from focal adhesions, which starts focal adhesion turnover.

scholarly journals The SOCS-Box of HIV-1 Vif Interacts with ElonginBC by Induced-Folding to Recruit Its Cul5-Containing Ubiquitin Ligase Complex

2010 ◽  
Vol 6 (6) ◽  
pp. e1000925 ◽  
Author(s):  
Julien R. C. Bergeron ◽  
Hendrik Huthoff ◽  
Dennis A. Veselkov ◽  
Rebecca L. Beavil ◽  
Peter J. Simpson ◽  
...  
Keyword(s):  
Ubiquitin Ligase ◽  
Induced Folding ◽  
Ubiquitin Ligase Complex ◽  
Socs Box ◽  
Hiv 1

scholarly journals Degradation-Independent Inhibition of APOBEC3G by the HIV-1 Vif Protein

Viruses ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 617
Author(s):  
Benjamin Stupfler ◽  
Cédric Verriez ◽  
Sarah Gallois-Montbrun ◽  
Roland Marquet ◽  
Jean-Christophe Paillart
Keyword(s):  
Molecular Mechanisms ◽  
Viral Infections ◽  
Current Knowledge ◽  
Ubiquitin Proteasome System ◽  
Restriction Factors ◽  
Ubiquitin Ligase Complex ◽  
Ubiquitin Proteasome ◽  
Viral Infectivity Factor ◽  
Vif Protein ◽  
Hiv 1

The ubiquitin–proteasome system plays an important role in the cell under normal physiological conditions but also during viral infections. Indeed, many auxiliary proteins from the (HIV-1) divert this system to its own advantage, notably to induce the degradation of cellular restriction factors. For instance, the HIV-1 viral infectivity factor (Vif) has been shown to specifically counteract several cellular deaminases belonging to the apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like (APOBEC3 or A3) family (A3A to A3H) by recruiting an E3-ubiquitin ligase complex and inducing their polyubiquitination and degradation through the proteasome. Although this pathway has been extensively characterized so far, Vif has also been shown to impede A3s through degradation-independent processes, but research on this matter remains limited. In this review, we describe our current knowledge regarding the degradation-independent inhibition of A3s, and A3G in particular, by the HIV-1 Vif protein, the molecular mechanisms involved, and highlight important properties of this small viral protein.

scholarly journals Chemical Synthesis and NMR Solution Structure of Conotoxin GXIA from Conus geographus

Marine Drugs ◽  
2021 ◽  
Vol 19 (2) ◽  
pp. 60
Author(s):  
David A. Armstrong ◽  
Ai-Hua Jin ◽  
Nayara Braga Emidio ◽  
Richard J. Lewis ◽  
Paul F. Alewood ◽  
...  
Keyword(s):  
Solution Structure ◽  
3D Structure ◽  
Voltage Sensor ◽  
Solution Nmr ◽  
Striking Similarity ◽  
Amino Acid Peptide ◽  
Wide Range ◽  
Cone Snails ◽  
Drug Leads ◽  
Β Sheet

Conotoxins are disulfide-rich peptides found in the venom of cone snails. Due to their exquisite potency and high selectivity for a wide range of voltage and ligand gated ion channels they are attractive drug leads in neuropharmacology. Recently, cone snails were found to have the capability to rapidly switch between venom types with different proteome profiles in response to predatory or defensive stimuli. A novel conotoxin, GXIA (original name G117), belonging to the I3-subfamily was identified as the major component of the predatory venom of piscivorous Conus geographus. Using 2D solution NMR spectroscopy techniques, we resolved the 3D structure for GXIA, the first structure reported for the I3-subfamily and framework XI family. The 32 amino acid peptide is comprised of eight cysteine residues with the resultant disulfide connectivity forming an ICK+1 motif. With a triple stranded β-sheet, the GXIA backbone shows striking similarity to several tarantula toxins targeting the voltage sensor of voltage gated potassium and sodium channels. Supported by an amphipathic surface, the structural evidence suggests that GXIA is able to embed in the membrane and bind to the voltage sensor domain of a putative ion channel target.

Modeling and solution structure probing of the HIV-1 TAR stem-loop

1993 ◽  
Vol 11 (2) ◽  
pp. 92-97 ◽  
Author(s):  
Andrew D. Critchley ◽  
I. Haneef ◽  
Diane J. Cousens ◽  
Peter G. Stockley
Keyword(s):  
Solution Structure ◽  
Stem Loop ◽  
Structure Probing ◽  
Hiv 1

scholarly journals The antiviral factor APOBEC3G improves CTL recognition of cultured HIV-infected T cells

2009 ◽  
Vol 207 (1) ◽  
pp. 39-49 ◽  
Author(s):  
Nicoletta Casartelli ◽  
Florence Guivel-Benhassine ◽  
Romain Bouziat ◽  
Samantha Brandler ◽  
Olivier Schwartz ◽  
...  
Keyword(s):  
Cytidine Deaminase ◽  
Adaptive Immune System ◽  
Antiviral Effect ◽  
Inhibitory Effect ◽  
Hiv Replication ◽  
Viral Infectivity Factor ◽  
Cellular Immune ◽  
Vif Protein ◽  
The Impact ◽  
Hiv 1

The cytidine deaminase APOBEC3G (A3G) enzyme exerts an intrinsic anti–human immunodeficiency virus (HIV) defense by introducing lethal G-to-A hypermutations in the viral genome. The HIV-1 viral infectivity factor (Vif) protein triggers degradation of A3G and counteracts this antiviral effect. The impact of A3G on the adaptive cellular immune response has not been characterized. We examined whether A3G-edited defective viruses, which are known to express truncated or misfolded viral proteins, activate HIV-1–specific (HS) CD8+ cytotoxic T lymphocytes (CTLs). To this end, we compared the immunogenicity of cells infected with wild-type or Vif-deleted viruses in the presence or absence of the cytidine deaminase. The inhibitory effect of A3G on HIV replication was associated with a strong activation of cocultivated HS-CTLs. CTL activation was particularly marked with Vif-deleted HIV and with viruses harboring A3G. Enzymatically inactive A3G mutants failed to enhance CTL activation. We also engineered proviruses bearing premature stop codons in their genome as scars of A3G editing. These viruses were not infectious but potently activated HS-CTLs. Therefore, the pool of defective viruses generated by A3G represents an underestimated source of viral antigens. Our results reveal a novel function for A3G, acting not only as an intrinsic antiviral factor but also as an inducer of the adaptive immune system.

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