scholarly journals Structural Basis for Enhanced HIV-1 Neutralization by a Dimeric Immunoglobulin G Form of the Glycan-Recognizing Antibody 2G12

Cell Reports ◽  
2013 ◽  
Vol 5 (5) ◽  
pp. 1443-1455 ◽  
Author(s):  
Yunji Wu ◽  
Anthony P. West ◽  
Helen J. Kim ◽  
Matthew E. Thornton ◽  
Andrew B. Ward ◽  
...  
Keyword(s):  
Immunoglobulin G ◽  
Structural Basis ◽  
Hiv 1 ◽  
Antibody 2G12

scholarly journals Structural basis for pH-insensitive inhibition of immunoglobulin G recycling by an anti-neonatal Fc receptor antibody

2017 ◽  
Vol 292 (42) ◽  
pp. 17449-17460 ◽  
Author(s):  
Jon A. Kenniston ◽  
Brandy M. Taylor ◽  
Gregory P. Conley ◽  
Janja Cosic ◽  
Kris J. Kopacz ◽  
...  
Keyword(s):  
Immunoglobulin G ◽  
Fc Receptor ◽  
Structural Basis ◽  
Neonatal Fc Receptor ◽  
Receptor Antibody

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 Structural Basis for the Inhibition of RNase H Activity of HIV-1 Reverse Transcriptase by RNase H Active Site-Directed Inhibitors

2010 ◽  
Vol 84 (15) ◽  
pp. 7625-7633 ◽  
Author(s):  
Hua-Poo Su ◽  
Youwei Yan ◽  
G. Sridhar Prasad ◽  
Robert F. Smith ◽  
Christopher L. Daniels ◽  
...  
Keyword(s):  
Active Site ◽  
Thermal Denaturation ◽  
Binding Mode ◽  
Rnase H ◽  
New Drugs ◽  
Structural Basis ◽  
Independent Manner ◽  
Approved Drugs ◽  
Hiv 1 ◽  
Rapid Emergence

ABSTRACT HIV/AIDS continues to be a menace to public health. Several drugs currently on the market have successfully improved the ability to manage the viral burden in infected patients. However, new drugs are needed to combat the rapid emergence of mutated forms of the virus that are resistant to existing therapies. Currently, approved drugs target three of the four major enzyme activities encoded by the virus that are critical to the HIV life cycle. Although a number of inhibitors of HIV RNase H activity have been reported, few inhibit by directly engaging the RNase H active site. Here, we describe structures of naphthyridinone-containing inhibitors bound to the RNase H active site. This class of compounds binds to the active site via two metal ions that are coordinated by catalytic site residues, D443, E478, D498, and D549. The directionality of the naphthyridinone pharmacophore is restricted by the ordering of D549 and H539 in the RNase H domain. In addition, one of the naphthyridinone-based compounds was found to bind at a second site close to the polymerase active site and non-nucleoside/nucleotide inhibitor sites in a metal-independent manner. Further characterization, using fluorescence-based thermal denaturation and a crystal structure of the isolated RNase H domain reveals that this compound can also bind the RNase H site and retains the metal-dependent binding mode of this class of molecules. These structures provide a means for structurally guided design of novel RNase H inhibitors.

scholarly journals Structural Basis for Env Incorporation into HIV-1 Particles

Proceedings ◽  
2020 ◽  
Vol 50 (1) ◽  
pp. 114
Author(s):  
R. Elliot Murphy ◽  
Alexandra B. Samal ◽  
Gunnar Eastep ◽  
Ruba H. Ghanam ◽  
Peter E. Prevelige ◽  
...  
Keyword(s):  
Structural Characterization ◽  
Late Phase ◽  
Three Dimensional ◽  
Dimensional Structure ◽  
Structural Basis ◽  
Membrane Interactions ◽  
Env Protein ◽  
Gag Assembly ◽  
Hiv 1

During the late phase of the HIV-1 replication cycle, the Gag polyproteins are transported to the plasma membrane (PM) for assembly. Gag targeting and assembly on the PM is dependent on interactions between its matrix (MA) domain and phosphatidylinositol-4,5-bisphosphate (PI(4,5)P2). Subsequent to Gag assembly, the envelope (Env) protein is recruited to the PM for incorporation into virus particles. Evidence suggests that the incorporation of the Env protein is mediated by interactions between the MA domain of Gag and the cytoplasmic tail of the gp41 subunit of Env (gp41CT), a mechanism that remains to be elucidated. Trimerization of the MA domain of Gag appears to be an obligatory step for this interaction. The interplay between gp41CT, the MA trimer, and the membrane has yet to be determined. Our lab has pioneered methods and approaches to investigate, at the molecular level, how the retroviral MA domains of Gag interact with membranes, a key requirement for understanding the Gag assembly and Env incorporation. Herein, we devised innovative approaches that will enable the structural characterization of the gp41CT–MA–membrane interactions. We employed structural biology (NMR and cryo-electron microscopy, biophysical methods, and biochemical tools to generate a macromolecular picture of how the MA domain of Gag binds to the membrane and how it interacts with gp41CT. To this end, we: (i) determined the three-dimensional structure of HIV-1 gp41CT and characterized its interaction with the membrane, (ii) engineered trimeric constructs of gp41CT and the MA to recapitulate the native and functional states of the proteins, and (iii) utilized membrane nanodisc technology to anchor the MA and gp41CT proteins. Our studies will allow for a detailed structural characterization of the gp41CT–MA–membrane interactions, which will advance our knowledge of HIV-1 Gag assembly and Env incorporation.

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