6l0c: Difference between revisions

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==Crystal structure of HIV-1 Integrase catalytic core domain (A128T/K173Q/F185K)==

== Structural highlights ==

<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6L0C OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6L0C FirstGlance]. <br>

<table><tr><td colspan='2'>[[6l0c]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Human_immunodeficiency_virus_1 Human immunodeficiency virus 1]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6L0C OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6L0C FirstGlance]. <br>

</td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=6l0c FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6l0c OCA], [https://pdbe.org/6l0c PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6l0c RCSB], [https://www.ebi.ac.uk/pdbsum/6l0c PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6l0c ProSAT]</span></td></tr>

</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.101Å</td></tr>

<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ARS:ARSENIC'>ARS</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>

<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=6l0c FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6l0c OCA], [https://pdbe.org/6l0c PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6l0c RCSB], [https://www.ebi.ac.uk/pdbsum/6l0c PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6l0c ProSAT]</span></td></tr>

</table>

== Function ==

[https://www.uniprot.org/uniprot/Q76353_9HIV1 Q76353_9HIV1]

== Publication Abstract from PubMed ==

HIV-1 often acquires drug-resistant mutations in spite of the benefits of antiretroviral therapy (ART). HIV-1 integrase (IN) is essential for the concerted integration of HIV-1 DNA into the host genome. IN further contributes to HIV-1 RNA binding, which is required for HIV-1 maturation. Non-catalytic-site integrase inhibitors (NCINIs) have been developed as allosteric IN inhibitors, which perform anti-HIV-1 activity by a multimodal mode of action such as inhibition of the IN-lens epithelium-derived growth factor (LEDGF)/p75 interaction in the early stage and disruption of functional IN multimerization in the late stage of HIV-1 replication. Here, we show that IN undergoes an adaptable conformational change to escape from NCINIs. We observed that NCINI-resistant HIV-1 variants have accumulated 4 amino acid mutations by passage 26 (P26) in the IN-encoding region. We employed high-performance liquid chromatography (HPLC), thermal stability assays, and X-ray crystallographic analysis to show that some amino acid mutations affect the stability and/or dimerization interface of the IN catalytic core domains (CCDs), potentially resulting in the severely decreased multimerization of full-length IN proteins (IN undermultimerization). This undermultimerized IN via NCINI-related mutations was stabilized by HIV-1 RNA and restored to the same level as that of wild-type HIV-1 in viral particles. Recombinant HIV-1 clones with IN undermultimerization propagated similarly to wild-type HIV-1. Our study revealed that HIV-1 can eventually counteract NCINI-induced IN overmultimerization by IN undermultimerization as one of the escape mechanisms. Our findings provide information on the understanding of IN multimerization with or without HIV-1 RNA and may influence the development of anti-HIV-1 strategies.IMPORTANCE Understanding the mechanism of HIV-1 resistance to anti-HIV-1 drugs could lead to the development of novel drugs with increased efficiency, resulting in more effective ART. ART composed of more potent and long-acting anti-HIV-1 drugs can greatly improve drug adherence and also provide HIV-1 prevention such as preexposure prophylaxis. NCINIs with a multimodal mode of action exert potent anti-HIV-1 effects through IN overmultimerization during HIV-1 maturation. However, HIV-1 can acquire some mutations that cause IN undermultimerization to alleviate NCINI-induced IN overmultimerization. This undermultimerized IN was efficiently stabilized by HIV-1 RNA and restored to the same level as that of wild-type HIV-1. Our findings revealed that HIV-1 eventually acquires such a conformational escape reaction to overcome the unique NCINI actions. The investigation into drug-resistant mutations associated with HIV-1 protein multimerization may facilitate the elucidation of its molecular mechanism and functional multimerization, allowing us to develop more potent anti-HIV-1 drugs and unique treatment strategies.

A Conformational Escape Reaction of HIV-1 against an Allosteric Integrase Inhibitor.,Nakamura T, Nakamura T, Amano M, Miyakawa T, Yamagata Y, Matsuoka M, Nakata H J Virol. 2020 Sep 15;94(19). pii: JVI.00486-20. doi: 10.1128/JVI.00486-20. Print , 2020 Sep 15. PMID:32611758<ref>PMID:32611758</ref>

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>

</div>

==See Also==

*[[Retroviral integrase 3D structures|Retroviral integrase 3D structures]]

== References ==

__TOC__

</StructureSection>

[[Category: Human immunodeficiency virus 1]]

[[Category: Large Structures]]

[[Category: Nakamura T]]

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@@ Line 1: / Line 1: @@
 ==Crystal structure of HIV-1 Integrase catalytic core domain (A128T/K173Q/F185K)==
-<StructureSection load='6l0c' size='340' side='right'caption='[[6l0c]]' scene=''>
+<StructureSection load='6l0c' size='340' side='right'caption='[[6l0c]], [[Resolution|resolution]] 2.10&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6L0C OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6L0C FirstGlance]. <br>
+<table><tr><td colspan='2'>[[6l0c]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Human_immunodeficiency_virus_1 Human immunodeficiency virus 1]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6L0C OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6L0C FirstGlance]. <br>
-</td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=6l0c FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6l0c OCA], [https://pdbe.org/6l0c PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6l0c RCSB], [https://www.ebi.ac.uk/pdbsum/6l0c PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6l0c ProSAT]</span></td></tr>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.101&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ARS:ARSENIC'>ARS</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=6l0c FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6l0c OCA], [https://pdbe.org/6l0c PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6l0c RCSB], [https://www.ebi.ac.uk/pdbsum/6l0c PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6l0c ProSAT]</span></td></tr>
 </table>
+== Function ==
+[https://www.uniprot.org/uniprot/Q76353_9HIV1 Q76353_9HIV1]
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+HIV-1 often acquires drug-resistant mutations in spite of the benefits of antiretroviral therapy (ART). HIV-1 integrase (IN) is essential for the concerted integration of HIV-1 DNA into the host genome. IN further contributes to HIV-1 RNA binding, which is required for HIV-1 maturation. Non-catalytic-site integrase inhibitors (NCINIs) have been developed as allosteric IN inhibitors, which perform anti-HIV-1 activity by a multimodal mode of action such as inhibition of the IN-lens epithelium-derived growth factor (LEDGF)/p75 interaction in the early stage and disruption of functional IN multimerization in the late stage of HIV-1 replication. Here, we show that IN undergoes an adaptable conformational change to escape from NCINIs. We observed that NCINI-resistant HIV-1 variants have accumulated 4 amino acid mutations by passage 26 (P26) in the IN-encoding region. We employed high-performance liquid chromatography (HPLC), thermal stability assays, and X-ray crystallographic analysis to show that some amino acid mutations affect the stability and/or dimerization interface of the IN catalytic core domains (CCDs), potentially resulting in the severely decreased multimerization of full-length IN proteins (IN undermultimerization). This undermultimerized IN via NCINI-related mutations was stabilized by HIV-1 RNA and restored to the same level as that of wild-type HIV-1 in viral particles. Recombinant HIV-1 clones with IN undermultimerization propagated similarly to wild-type HIV-1. Our study revealed that HIV-1 can eventually counteract NCINI-induced IN overmultimerization by IN undermultimerization as one of the escape mechanisms. Our findings provide information on the understanding of IN multimerization with or without HIV-1 RNA and may influence the development of anti-HIV-1 strategies.IMPORTANCE Understanding the mechanism of HIV-1 resistance to anti-HIV-1 drugs could lead to the development of novel drugs with increased efficiency, resulting in more effective ART. ART composed of more potent and long-acting anti-HIV-1 drugs can greatly improve drug adherence and also provide HIV-1 prevention such as preexposure prophylaxis. NCINIs with a multimodal mode of action exert potent anti-HIV-1 effects through IN overmultimerization during HIV-1 maturation. However, HIV-1 can acquire some mutations that cause IN undermultimerization to alleviate NCINI-induced IN overmultimerization. This undermultimerized IN was efficiently stabilized by HIV-1 RNA and restored to the same level as that of wild-type HIV-1. Our findings revealed that HIV-1 eventually acquires such a conformational escape reaction to overcome the unique NCINI actions. The investigation into drug-resistant mutations associated with HIV-1 protein multimerization may facilitate the elucidation of its molecular mechanism and functional multimerization, allowing us to develop more potent anti-HIV-1 drugs and unique treatment strategies.
+A Conformational Escape Reaction of HIV-1 against an Allosteric Integrase Inhibitor.,Nakamura T, Nakamura T, Amano M, Miyakawa T, Yamagata Y, Matsuoka M, Nakata H J Virol. 2020 Sep 15;94(19). pii: JVI.00486-20. doi: 10.1128/JVI.00486-20. Print , 2020 Sep 15. PMID:32611758<ref>PMID:32611758</ref>
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
+</div>
+<div class="pdbe-citations 6l0c" style="background-color:#fffaf0;"></div>
 ==See Also==
 *[[Retroviral integrase 3D structures|Retroviral integrase 3D structures]]
+== References ==
+<references/>
 __TOC__
 </StructureSection>
+[[Category: Human immunodeficiency virus 1]]
 [[Category: Large Structures]]
 [[Category: Nakamura T]]