Gp120: Difference between revisions
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<StructureSection load='' size=' | <StructureSection load='' size='350' side='right' scene='Journal:JBSD:41/Cv/1' caption='HIV Gp120 (green) complex with human T-cell surface glycoprotein CD4 (yellow) (PDB code [[1rzj]])'> | ||
== Function == | == Function == | ||
'''Glycoprotein Gp120''', named for its molecular weight, is found on the surface of HIV envelope. Gp120 is associated with Gp41. It is involved in the binding of HIV to CD4 receptors thus attaching the virus to the host cell<ref>PMID:11244037</ref>. For more details see<br /> | '''Glycoprotein Gp120''', named for its molecular weight, is found on the surface of HIV envelope. Gp120 is associated with Gp41. It is involved in the binding of HIV to CD4 receptors thus attaching the virus to the host cell<ref>PMID:11244037</ref>. For more details see<br /> | ||
*[[Hiv env proteins]]<br /> | *[[Hiv env proteins|HIV-1 viral envelope proteins]]<br /> | ||
*[[VRC01 gp120 complex]]. | *[[VRC01 gp120 complex]]. | ||
== Structural highlights == | == Structural highlights == | ||
In HIV the third variable loop (V3) residues 296-331 of Gp120 allows the virus to infect human immune cells. | In HIV <scene name='49/490076/Cv/11'>the third variable loop (V3) residues 296-331 of Gp120</scene> allows the virus to infect human immune cells. | ||
== Molecular Mechanism of HIV-1 gp120 Mutations That Reduce CD4 Binding Affinity <ref>doi 10.1080/07391102.2012.746946</ref>== | == Molecular Mechanism of HIV-1 gp120 Mutations That Reduce CD4 Binding Affinity <ref>doi 10.1080/07391102.2012.746946</ref>== | ||
Despite abundant efforts in HIV research the HI-virus remains one of the most serious infectious health threats for human worldwide. Infection involves the entry of the virus into CD4 carrying cells and is mediated by the recognition of the <scene name='Journal:JBSD:41/Cv/2'>cellular CD4 surface protein</scene> (<span style="color:yellow;background-color:black;font-weight:bold;">colored in yellow</span>) by <scene name='Journal:JBSD:41/Cv/3'>gp120 of the viral envelope</scene> (<span style="color:lime;background-color:black;font-weight:bold;">colored in green</span>). The CD4-binding site of gp120 contains <scene name='Journal:JBSD:41/Cv/4'>two crucial loops</scene>, termed the <font color='blue'><b>‘CD4-binding loop’ (in blue)</b></font> and the <span style="color:salmon;background-color:black;font-weight:bold;">‘outer domain exit (ODE) loop’ (colored in salmon)</span>, respectively. Importantly, <scene name='Journal:JBSD:41/Cv/6'>this functional site</scene> is a key target site for gp120-ligands to interfere with the gp120-CD4 interaction and thereby hampering infection. <span style="color:white;background-color:black;font-weight:bold;">Carbons of the important residues are colored in white</span>, <font color='blue'><b>nitrogens in blue</b></font>, and <font color='red'><b>oxygens in red</b></font>. Therapeutic ligands include for instance soluble CD4 and its variants. | Despite abundant efforts in HIV research the HI-virus remains one of the most serious infectious health threats for human worldwide. Infection involves the entry of the virus into CD4 carrying cells and is mediated by the recognition of the <scene name='Journal:JBSD:41/Cv/2'>cellular CD4 surface protein</scene> (<span style="color:yellow;background-color:black;font-weight:bold;">colored in yellow</span>) by <scene name='Journal:JBSD:41/Cv/3'>gp120 of the viral envelope</scene> (<span style="color:lime;background-color:black;font-weight:bold;">colored in green</span>). The CD4-binding site of gp120 contains <scene name='Journal:JBSD:41/Cv/4'>two crucial loops</scene>, termed the <font color='blue'><b>‘CD4-binding loop’ (in blue)</b></font> and the <span style="color:salmon;background-color:black;font-weight:bold;">‘outer domain exit (ODE) loop’ (colored in salmon)</span>, respectively. Importantly, <scene name='Journal:JBSD:41/Cv/6'>this functional site</scene> is a key target site for gp120-ligands to interfere with the gp120-CD4 interaction and thereby hampering infection. <span style="color:white;background-color:black;font-weight:bold;">Carbons of the important residues are colored in white</span>, <font color='blue'><b>nitrogens in blue</b></font>, and <font color='red'><b>oxygens in red</b></font>. Therapeutic ligands include for instance soluble CD4 and its variants. | ||
For the development of more potent gp120-ligands targeting the CD4-binding site we investigated two gp120-proteins from two clinical HIV isolates that exhibit a decreased affinity for soluble CD4. Each variant exhibits a set of simultaneous mutations in the CD4-binding loop and the ODE-loop. The <scene name='Journal:JBSD:41/Cv/7'>mutant gp120(3-2)</scene> exhibits three mutations in the CD4-binding loop (P369A, I371L, T373M) and two mutations in the ODE-loop (G471E, D474N). The <scene name='Journal:JBSD:41/Cv/8'>gp120(2-1)</scene> protein contains three simultaneous mutations: V372E, T373M in the CD4-binding loop, and D474N in the ODE-loop. <font color='magenta'><b>Carbons of the mutated residues are colored in white</b></font>, <font color='blue'><b>nitrogens in blue</b></font>, <font color='red'><b>oxygens in red</b></font>, and <span style="color:yellow;background-color:black;font-weight:bold;">sulfur in yellow</span>. To understand the phenomenon of reduced CD4-binding on a structural level the two gp120 variants were modeled, each with its specific set of mutations, and simulated using molecular dynamics. The results show that the mutant glutamates of both variants play a key role for reduced CD4 binding by affecting the conformation of the CD4-binding and ODE-loop. This knowledge should be helpful to predict the resistance of novel gp120 mutants or to design gp120-ligands with improved binding properties. | For the development of more potent gp120-ligands targeting the CD4-binding site we investigated two gp120-proteins from two clinical HIV isolates that exhibit a decreased affinity for soluble CD4. Each variant exhibits a set of simultaneous mutations in the CD4-binding loop and the ODE-loop. The <scene name='Journal:JBSD:41/Cv/7'>mutant gp120(3-2)</scene> exhibits three mutations in the CD4-binding loop (P369A, I371L, T373M) and two mutations in the ODE-loop (G471E, D474N). The <scene name='Journal:JBSD:41/Cv/8'>gp120(2-1)</scene> protein contains three simultaneous mutations: V372E, T373M in the CD4-binding loop, and D474N in the ODE-loop. <font color='magenta'><b>Carbons of the mutated residues are colored in white</b></font>, <font color='blue'><b>nitrogens in blue</b></font>, <font color='red'><b>oxygens in red</b></font>, and <span style="color:yellow;background-color:black;font-weight:bold;">sulfur in yellow</span>. To understand the phenomenon of reduced CD4-binding on a structural level the two gp120 variants were modeled, each with its specific set of mutations, and simulated using molecular dynamics. The results show that the mutant glutamates of both variants play a key role for reduced CD4 binding by affecting the conformation of the CD4-binding and ODE-loop. This knowledge should be helpful to predict the resistance of novel gp120 mutants or to design gp120-ligands with improved binding properties. | ||
==3D structures of Gp120== | ==3D structures of Gp120== | ||
[[Gp120 3D structures]] | |||
</StructureSection> | |||
== References == | == References == | ||
Latest revision as of 17:55, 17 November 2019
FunctionGlycoprotein Gp120, named for its molecular weight, is found on the surface of HIV envelope. Gp120 is associated with Gp41. It is involved in the binding of HIV to CD4 receptors thus attaching the virus to the host cell[1]. For more details see Structural highlightsIn HIV allows the virus to infect human immune cells. Molecular Mechanism of HIV-1 gp120 Mutations That Reduce CD4 Binding Affinity [2]Despite abundant efforts in HIV research the HI-virus remains one of the most serious infectious health threats for human worldwide. Infection involves the entry of the virus into CD4 carrying cells and is mediated by the recognition of the (colored in yellow) by (colored in green). The CD4-binding site of gp120 contains , termed the ‘CD4-binding loop’ (in blue) and the ‘outer domain exit (ODE) loop’ (colored in salmon), respectively. Importantly, is a key target site for gp120-ligands to interfere with the gp120-CD4 interaction and thereby hampering infection. Carbons of the important residues are colored in white, nitrogens in blue, and oxygens in red. Therapeutic ligands include for instance soluble CD4 and its variants. For the development of more potent gp120-ligands targeting the CD4-binding site we investigated two gp120-proteins from two clinical HIV isolates that exhibit a decreased affinity for soluble CD4. Each variant exhibits a set of simultaneous mutations in the CD4-binding loop and the ODE-loop. The exhibits three mutations in the CD4-binding loop (P369A, I371L, T373M) and two mutations in the ODE-loop (G471E, D474N). The protein contains three simultaneous mutations: V372E, T373M in the CD4-binding loop, and D474N in the ODE-loop. Carbons of the mutated residues are colored in white, nitrogens in blue, oxygens in red, and sulfur in yellow. To understand the phenomenon of reduced CD4-binding on a structural level the two gp120 variants were modeled, each with its specific set of mutations, and simulated using molecular dynamics. The results show that the mutant glutamates of both variants play a key role for reduced CD4 binding by affecting the conformation of the CD4-binding and ODE-loop. This knowledge should be helpful to predict the resistance of novel gp120 mutants or to design gp120-ligands with improved binding properties. 3D structures of Gp120
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ReferencesReferences
- ↑ Poignard P, Saphire EO, Parren PW, Burton DR. gp120: Biologic aspects of structural features. Annu Rev Immunol. 2001;19:253-74. PMID:11244037 doi:http://dx.doi.org/10.1146/annurev.immunol.19.1.253
- ↑ Kassler K, Sticht H. Molecular mechanism of HIV-1 gp120 mutations that reduce CD4 binding affinity. J Biomol Struct Dyn. 2013 Jan 9. PMID:23297802 doi:10.1080/07391102.2012.746946