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| | <StructureSection load='5y14' size='340' side='right'caption='[[5y14]], [[Resolution|resolution]] 1.76Å' scene=''> | | <StructureSection load='5y14' size='340' side='right'caption='[[5y14]], [[Resolution|resolution]] 1.76Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5y14]] is a 6 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5Y14 OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=5Y14 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5y14]] is a 6 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=5Y14 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5Y14 FirstGlance]. <br> |
| - | </td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=5y14 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5y14 OCA], [http://pdbe.org/5y14 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5y14 RCSB], [http://www.ebi.ac.uk/pdbsum/5y14 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5y14 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]] 1.762Å</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=5y14 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5y14 OCA], [https://pdbe.org/5y14 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5y14 RCSB], [https://www.ebi.ac.uk/pdbsum/5y14 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5y14 ProSAT]</span></td></tr> |
| | </table> | | </table> |
| - | <div style="background-color:#fffaf0;">
| + | == Function == |
| - | == Publication Abstract from PubMed == | + | [https://www.uniprot.org/uniprot/Q1HMR5_9HIV1 Q1HMR5_9HIV1] |
| - | The peptide drug enfuvirtide (T20) is the only viral fusion inhibitor used in combination therapy for HIV-1 infection, but it has relatively low antiviral activity and easily induces drug resistance. Emerging studies demonstrate that lipopeptide-based fusion inhibitors, such as LP-11 and LP-19, which mainly target the gp41 pocket site, have greatly improved antiviral potency and in vivo stability. In this study, we focused on developing a T20-based lipopeptide inhibitor that lacks pocket-binding sequence and targets a different site. First, the C-terminal tryptophan-rich motif (TRM) of T20 was verified to be essential for its target binding and inhibition; then, a novel lipopeptide, termed LP-40, was created by replacing the TRM with a fatty acid group. LP-40 showed markedly enhanced binding affinity for the target site and dramatically increased inhibitory activity on HIV-1 membrane fusion, entry, and infection. Unlike LP-11 and LP-19, which required a flexible linker between the peptide sequence and the lipid moiety, addition of a linker to LP-40 sharply reduced its potency, implying different binding modes with the extended N-terminal helices of gp41. Also, interestingly, LP-40 showed more potent activity than LP-11 in inhibiting HIV-1 Env-mediated cell-cell fusion while it was less active than LP-11 in inhibiting pseudovirus entry, and the two inhibitors displayed synergistic antiviral effects. The crystal structure of LP-40 in complex with a target peptide revealed their key binding residues and motifs. Combined, our studies have not only provided a potent HIV-1 fusion inhibitor, but also revealed new insights into the mechanisms of viral inhibition.IMPORTANCE T20 is the only membrane fusion inhibitor available for treatment of viral infection; however, T20 requires high doses and has a low genetic barrier for resistance, and its inhibitory mechanism and structural basis remain unclear. Here, we report the design of LP-40, a T20-based lipopeptide inhibitor that has greatly improved anti-HIV activity and is a more potent inhibitor of cell-cell fusion than of cell-free virus infection. The binding modes of two classes of membrane-anchoring lipopeptides (LP-40 and LP-11) verify the current fusion model in which an extended prehairpin structure bridges the viral and cellular membranes, and their complementary effects suggest a vital strategy for combination therapy of HIV-1 infection. Moreover, our understanding of the mechanism of action of T20 and its derivatives benefits from the crystal structure of LP-40.
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| - | | + | |
| - | Enfuvirtide (T20)-Based Lipopeptide Is a Potent HIV-1 Cell Fusion Inhibitor: Implications for Viral Entry and Inhibition.,Ding X, Zhang X, Chong H, Zhu Y, Wei H, Wu X, He J, Wang X, He Y J Virol. 2017 Aug 24;91(18). pii: e00831-17. doi: 10.1128/JVI.00831-17. Print, 2017 Sep 15. PMID:28659478<ref>PMID:28659478</ref>
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| - | | + | |
| - | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
| + | |
| - | </div>
| + | |
| - | <div class="pdbe-citations 5y14" style="background-color:#fffaf0;"></div>
| + | |
| - | == References ==
| + | |
| - | <references/>
| + | |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| | + | [[Category: Human immunodeficiency virus 1]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: He, Y]] | + | [[Category: He Y]] |
| - | [[Category: Wang, X]] | + | [[Category: Wang X]] |
| - | [[Category: Zhang, X]] | + | [[Category: Zhang X]] |
| - | [[Category: 6-hb]]
| + | |
| - | [[Category: Hiv-1]]
| + | |
| - | [[Category: Viral protein-inhibitor complex]]
| + | |
