scholarly journals Modeling of CCR5 Recognition by HIV-1 gp120: How the Viral Protein Exploits the Conformational Plasticity of the Coreceptor

Viruses ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 1395
Author(s):  
Célien Jacquemard ◽  
Florian Koensgen ◽  
Philippe Colin ◽  
Bernard Lagane ◽  
Esther Kellenberger
Keyword(s):  
3D Structure ◽  
Cell Interaction ◽  
Site Directed Mutagenesis ◽  
Intracellular Loop ◽  
Conformational Ensembles ◽  
Chemokine Receptor Ccr5 ◽  
Binding Cavity ◽  
Protein Binding Region ◽  
Conformational Plasticity ◽  
Hiv 1

The chemokine receptor CCR5 is a key player in HIV-1 infection. The cryo-EM 3D structure of HIV-1 envelope glycoprotein (Env) subunit gp120 in complex with CD4 and CCR5 has provided important structural insights into HIV-1/host cell interaction, yet it has not explained the signaling properties of Env nor the fact that CCR5 exists in distinct forms that show distinct Env binding properties. We used classical molecular dynamics and site-directed mutagenesis to characterize the CCR5 conformations stabilized by four gp120s, from laboratory-adapted and primary HIV-1 strains, and which were previously shown to bind differentially to distinct CCR5 forms and to exhibit distinct cellular tropisms. The comparative analysis of the simulated structures reveals that the different gp120s do indeed stabilize CCR5 in different conformational ensembles. They differentially reorient extracellular loops 2 and 3 of CCR5 and thus accessibility to the transmembrane binding cavity. They also reshape this cavity differently and give rise to different positions of intracellular ends of transmembrane helices 5, 6 and 7 of the receptor and of its third intracellular loop, which may in turn influence the G protein binding region differently. These results suggest that the binding of gp120s to CCR5 may have different functional outcomes, which could result in different properties for viruses.

scholarly journals Color-tuning of natural variants of heliorhodopsin

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Se-Hwan Kim ◽  
Kimleng Chuon ◽  
Shin-Gyu Cho ◽  
Ahreum Choi ◽  
Seanghun Meas ◽  
...  
Keyword(s):  
3D Structure ◽  
Site Directed Mutagenesis ◽  
Type I ◽  
Transmembrane Helices ◽  
Color Tuning ◽  
Tuning Mechanism ◽  
Spectral Changes ◽  
His Tag ◽  
Natural Variants ◽  
Retinal Chromophore

AbstractMicrobial rhodopsins are distributed through many microorganisms. Heliorhodopsins are newly discovered but have an unclear function. They have seven transmembrane helices similar to type-I and type-II rhodopsins, but they are different in that the N-terminal region of heliorhodopsin is cytoplasmic. We chose 13 representative heliorhodopsins from various microorganisms, expressed and purified with an N-terminal His tag, and measured the absorption spectra. The 13 natural variants had an absorption maximum (λmax) in the range 530–556 nm similar to proteorhodopsin (λmax = 490–525 nm). We selected several candidate residues that influence rhodopsin color-tuning based on sequence alignment and constructed mutants via site-directed mutagenesis to confirm the spectral changes. We found two important residues located near retinal chromophore that influence λmax. We also predict the 3D structure via homology-modeling of Thermoplasmatales heliorhodopsin. The results indicate that the color-tuning mechanism of type-I rhodopsin can be applied to understand the color-tuning of heliorhodopsin.

scholarly journals New insights into structure and function of bis-phosphinic acid derivatives and implications for CFTR modulation

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Sara Bitam ◽  
Ahmad Elbahnsi ◽  
Geordie Creste ◽  
Iwona Pranke ◽  
Benoit Chevalier ◽  
...  
Keyword(s):  
Phosphinic Acid ◽  
Site Directed Mutagenesis ◽  
Side Chain ◽  
Transmembrane Conductance Regulator ◽  
Intracellular Loop ◽  
Respiratory Cells ◽  
Cftr Protein ◽  
Dynamics Simulations ◽  
And Function ◽  
Molecular Mode

AbstractC407 is a compound that corrects the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) protein carrying the p.Phe508del (F508del) mutation. We investigated the corrector effect of c407 and its derivatives on F508del-CFTR protein. Molecular docking and dynamics simulations combined with site-directed mutagenesis suggested that c407 stabilizes the F508del-Nucleotide Binding Domain 1 (NBD1) during the co-translational folding process by occupying the position of the p.Phe1068 side chain located at the fourth intracellular loop (ICL4). After CFTR domains assembly, c407 occupies the position of the missing p.Phe508 side chain. C407 alone or in combination with the F508del-CFTR corrector VX-809, increased CFTR activity in cell lines but not in primary respiratory cells carrying the F508del mutation. A structure-based approach resulted in the synthesis of an extended c407 analog G1, designed to improve the interaction with ICL4. G1 significantly increased CFTR activity and response to VX-809 in primary nasal cells of F508del homozygous patients. Our data demonstrate that in-silico optimized c407 derivative G1 acts by a mechanism different from the reference VX-809 corrector and provide insights into its possible molecular mode of action. These results pave the way for novel strategies aiming to optimize the flawed ICL4–NBD1 interface.

scholarly journals Defining HIV-1 Vif residues that interact with CBFβ by site-directed mutagenesis

Virology ◽  
2014 ◽  
Vol 449 ◽  
pp. 82-87 ◽  
Author(s):  
Yusuke Matsui ◽  
Keisuke Shindo ◽  
Kayoko Nagata ◽  
Katsuhiro Io ◽  
Kohei Tada ◽  
...  
Keyword(s):  
Site Directed Mutagenesis ◽  
Directed Mutagenesis ◽  
Hiv 1

scholarly journals Computational Analysis of Molecular Interaction Networks Underlying Change of HIV-1 Resistance to Selected Reverse Transcriptase Inhibitors

2010 ◽  
Vol 4 ◽  
pp. BBI.S6247 ◽  
Author(s):  
Marcin Kierczak ◽  
Michał Dramiński ◽  
Jacek Koronacki ◽  
Jan Komorowski
Keyword(s):  
Drug Resistance ◽  
Reverse Transcriptase ◽  
Molecular Interaction ◽  
3D Structure ◽  
Resistance Mechanisms ◽  
Interaction Networks ◽  
Resistance Level ◽  
Molecular Interaction Networks ◽  
Monte Carlo Feature Selection ◽  
Hiv 1

Motivation Despite more than two decades of research, HIV resistance to drugs remains a serious obstacle in developing efficient AIDS treatments. Several computational methods have been developed to predict resistance level from the sequence of viral proteins such as reverse transcriptase (RT) or protease. These methods, while powerful and accurate, give very little insight into the molecular interactions that underly acquisition of drug resistance/hypersusceptibility. Here, we attempt at filling this gap by using our Monte Carlo feature selection and interdependency discovery method (MCFS-ID) to elucidate molecular interaction networks that characterize viral strains with altered drug resistance levels. Results We analyzed a number of HIV-1 RT sequences annotated with drug resistance level using the MCFS-ID method. This let us expound interdependency networks that characterize change of drug resistance to six selected RT inhibitors: Abacavir, Lamivudine, Stavudine, Zidovudine, Tenofovir and Nevirapine. The networks consider interdependencies at the level of physicochemical properties of mutating amino acids, eg,: polarity. We mapped each network on the 3D structure of RT in attempt to understand the molecular meaning of interacting pairs. The discovered interactions describe several known drug resistance mechanisms and, importantly, some previously unidentified ones. Our approach can be easily applied to a whole range of problems from the domain of protein engineering. Availability A portable Java implementation of our MCFS-ID method is freely available for academic users and can be obtained at: http://www.ipipan.eu/staff/m.draminski/software.htm .

scholarly journals Structural insights into the conformational plasticity of the full-length trimeric HIV-1 envelope glycoprotein precursor

2018 ◽  
Author(s):  
Shijian Zhang ◽  
Wei Li Wang ◽  
Shuobing Chen ◽  
Maolin Lu ◽  
Eden P. Go ◽  
...  
Keyword(s):  
Viral Entry ◽  
Envelope Glycoprotein ◽  
Structural Data ◽  
Full Length ◽  
Heptad Repeat ◽  
Structural Basis ◽  
Glycoprotein Precursor ◽  
Helix Bundle ◽  
Conformational Plasticity ◽  
Hiv 1

SummaryThe human immunodeficiency virus (HIV-1) envelope glycoprotein (Env) trimer mediates viral entry into cells and is the major target for the host antibody response. In infected cells, the mature Env [(gp120/gp41)3] is produced by cleavage of a trimeric gp160 precursor. Proteolytic cleavage decreases Env conformational flexibility, allowing the mature Env to resist antibody binding to conserved elements. The conformational plasticity of the Env precursor skews the humoral immune response towards the elicitation of ineffectual antibodies, contributing to HIV-1 persistence in the infected host. The structural basis for the plasticity of the Env precursor remains elusive. Here we use cryo-electron microscopy to visualize two coexisting conformational states of the full-length Env precursor at nominal resolutions of 5.5 and 8.0 Å. The State-P2 conformation features a three-helix bundle of the gp41 heptad repeat region in the core, but has disordered membrane-interactive regions. State-P1 trimers lack the three-helix bundle and instead retain ordered transmembrane and membrane-proximal external regions embracing a central cavity. Our structural data shed light on the unusual plasticity of the Env precursor and provide new clues to Env immunogen discovery.

scholarly journals A Mutation in Human Immunodeficiency Virus Type 1 Protease, N88S, That Causes In Vitro Hypersensitivity to Amprenavir

2000 ◽  
Vol 74 (9) ◽  
pp. 4414-4419 ◽  
Author(s):  
Rainer Ziermann ◽  
Kay Limoli ◽  
Kalyan Das ◽  
Edward Arnold ◽  
Christos J. Petropoulos ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Salvage Therapy ◽  
The United States ◽  
Site Directed Mutagenesis ◽  
Cross Resistance ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT Amprenavir (Agenerase, 141-W94, VX-478) is a human immunodeficiency virus type 1 (HIV-1) protease inhibitor (PRI) recently approved for the treatment of HIV-1 infection in the United States. A major cause of treatment failure is the development of resistance to PRIs. One potential use for amprenavir is as salvage therapy for patients for whom treatment that includes one (or more) of the other four currently approved PRIs—saquinavir, indinavir, ritonavir, and nelfinavir—has failed. We evaluated the cross-resistance to amprenavir of viruses that evolved during treatment with the two most commonly prescribed PRIs, nelfinavir and indinavir. Unexpectedly, a dramatic increase in susceptibility (2.5- to 12.5-fold) was observed with 20 of 312 (6.4%) patient viruses analyzed. The most pronounced increases in susceptibility were strongly associated with an N88S mutation in protease. All viruses that carried the N88S mutation were hypersensitive to amprenavir. Site-directed mutagenesis studies confirmed the causal role of N88S in determining amprenavir hypersensitivity. The presence of the N88S mutation and associated amprenavir hypersensitivity may be useful in predicting an improved clinical response to amprenavir salvage therapy.

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