VRC01 gp120 complex: Difference between revisions
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<StructureSection load='3se9' size='450' side='right' scene='' caption='HIV-1 gp120 (gold) complex with antibody light chain (aqua), heavy chain (red), NAG, TRIS, glycerol butanediol and Cl- ion (PDB code [[3se9]])'> | |||
The crystal structure of VRC01 and VRC01-like antibodies are studied to define with characteristics are important in neutralizing HIV-1. | The crystal structure of VRC01 and VRC01-like antibodies are studied to define with characteristics are important in neutralizing HIV-1. | ||
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<scene name='52/521911/Cv/2'>VRC-PG04 heavy chain (gold) and light chain (aqua) in complex with gp120 (red)</scene> ([[3se9]]). | |||
==Introduction== | ==Introduction== | ||
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HIV-1 enters its host by binding viral gp120, a surface glycoprotein of HIV, to the host cell’s CD4 receptor. This interaction induces conformational changes in gp120<ref name="wu" />. This conformational change results in the exposure of a binding site for the co-receptor, usually CCR5 OR CXCR4<ref>PMID: 21715490</ref>. The conformational changes also result in the formation of a pre-hairpin intermediate conformation in which gp41, a transmembrane glycoprotein of HIV, rearranges its molecules so that its N-terminal peptides form a trimer of helices that present a fusion peptide to the target cell. Once fusion occurs between the fusion peptide and the target cell membrane, HIV is able to enter and infect the target cell<ref>PMID: 22807678</ref>. VRC01 binds to CD4’s binding site on gp120, preventing the CD4 receptor from binding to HIV and infecting the cell<ref name="wu" />. | HIV-1 enters its host by binding viral gp120, a surface glycoprotein of HIV, to the host cell’s CD4 receptor. This interaction induces conformational changes in gp120<ref name="wu" />. This conformational change results in the exposure of a binding site for the co-receptor, usually CCR5 OR CXCR4<ref>PMID: 21715490</ref>. The conformational changes also result in the formation of a pre-hairpin intermediate conformation in which gp41, a transmembrane glycoprotein of HIV, rearranges its molecules so that its N-terminal peptides form a trimer of helices that present a fusion peptide to the target cell. Once fusion occurs between the fusion peptide and the target cell membrane, HIV is able to enter and infect the target cell<ref>PMID: 22807678</ref>. VRC01 binds to CD4’s binding site on gp120, preventing the CD4 receptor from binding to HIV and infecting the cell<ref name="wu" />. | ||
==Structural Features== | ==Structural Features== | ||
<u>Similarities to CD4 in complex with gp120</u>. Analysis of VRC01 in complex with gp120 shows that this complex covers 98% of the CD4 binding site. However, VRC01’s binding site extends outside that of CD4, making it vulnerable to resistance of VRC01 neutralization by antigenic variation<ref name="zhou">PMID: 20616231</ref>. [[Image: Target Site.jpg | thumb | alt=text | Picture 1]] In Picture 1B, the contact surface of VRC01 and CD4 are shown on gp120. The green represents VRC01's contact surface and yellow represents CD4's contact surface<ref name="kwong" />. Both the heavy chain and light chain of VRC01 contribute to the contact surfaces of the VRC01 gp120 complex. The focus of the binding is on the heavy chain second complementary-determining region. Over 50% of the surface contact involves the heavy chain second complementary-determining region; this is similar to CD4’s interaction with gp120. Two dominant residues, Phe43 and Arg59, are involved in CD4’s binding to gp120. Of these two residues, only the arginine interaction is mimicked by VRC01. This dominant interaction is between Asp368 of gp120 and Arg59 of the CD4 receptor and between Asp368 of gp120 and Arg71 of VRC01. Arg71 and Asp368 form a <scene name='VRC01_gp120_complex/Salt_bridge/1'>salt bridge</scene><ref name="zhou" />. | <scene name='52/521911/Cv/3'>VRC01 heavy chain (gold, green, magenta, blue), light chain (aqua, pink, cyan, rust) in complex with gp120 (red, grey, yellow, wheat)</scene> ([[3ngb]]). | ||
<u>Similarities to CD4 in complex with gp120</u>. Analysis of VRC01 in complex with gp120 shows that this complex covers 98% of the CD4 binding site. However, VRC01’s binding site extends outside that of CD4, making it vulnerable to resistance of VRC01 neutralization by antigenic variation<ref name="zhou">PMID: 20616231</ref>. | |||
[[Image: Target Site.jpg | thumb | alt=text | Picture 1]] | |||
{{Clear}} | |||
In Picture 1B, the contact surface of VRC01 and CD4 are shown on gp120. The green represents VRC01's contact surface and yellow represents CD4's contact surface<ref name="kwong" />. Both the heavy chain and light chain of VRC01 contribute to the contact surfaces of the VRC01 gp120 complex. The focus of the binding is on the heavy chain second complementary-determining region. Over 50% of the surface contact involves the heavy chain second complementary-determining region; this is similar to CD4’s interaction with gp120. Two dominant residues, Phe43 and Arg59, are involved in CD4’s binding to gp120. Of these two residues, only the arginine interaction is mimicked by VRC01. This dominant interaction is between Asp368 of gp120 and Arg59 of the CD4 receptor and between Asp368 of gp120 and Arg71 of VRC01. Arg71 and Asp368 form a <scene name='VRC01_gp120_complex/Salt_bridge/1'>salt bridge</scene><ref name="zhou" />. | |||
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<u>Other features</u>. VRC01 light chain residues, <scene name='VRC01_gp120_complex/Tyr_28_and_ser_30/1'>Tyr28 and Ser30</scene>, make contacts with the protein-proximal N-acetyl-glucosamine from the N-linked glycan residue 276 of gp120. While other structures are blocked from binding because glycan shielding, VRC01 takes advantage of the glycan for binding<ref name="zhou" />. | <u>Other features</u>. VRC01 light chain residues, <scene name='VRC01_gp120_complex/Tyr_28_and_ser_30/1'>Tyr28 and Ser30</scene>, make contacts with the protein-proximal N-acetyl-glucosamine from the N-linked glycan residue 276 of gp120. While other structures are blocked from binding because glycan shielding, VRC01 takes advantage of the glycan for binding<ref name="zhou" />. | ||
==HIV Prevention Research== | ==HIV Prevention Research== | ||
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A similar experiment was done in 2012; it used humanized mouse models called RAG-hu mice, which contained human target cells. Results show that seven out of nine mice that were administered the VRC01 antibody and all mice that were given a cocktail containing four broadly neutralizing antibodies as a topical gel were protected against HIV-1. These results showed that broadly neutralizing antibodies could be used as a topical microbicide to prevent vaginal transmission of HIV and that a combination of antibodies can provide better protection against HIV. When the VRC01 antibody and the broadly neutralizing antibody cocktail were administered to the humanized mice via the intravenous route, none of the mice were infected with SHIV<ref>PMID: 22832125</ref>. | A similar experiment was done in 2012; it used humanized mouse models called RAG-hu mice, which contained human target cells. Results show that seven out of nine mice that were administered the VRC01 antibody and all mice that were given a cocktail containing four broadly neutralizing antibodies as a topical gel were protected against HIV-1. These results showed that broadly neutralizing antibodies could be used as a topical microbicide to prevent vaginal transmission of HIV and that a combination of antibodies can provide better protection against HIV. When the VRC01 antibody and the broadly neutralizing antibody cocktail were administered to the humanized mice via the intravenous route, none of the mice were infected with SHIV<ref>PMID: 22832125</ref>. | ||
</StructureSection> | |||
==References== | ==References== | ||
<references /> | <references /> | ||
