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5yc0

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Revision as of 09:15, 21 October 2020

Crystal structure of LP-46/N44

Structural highlights

5yc0 is a 12 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Publication Abstract from PubMed

Enfuvirtide (T20) is the only viral fusion inhibitor approved for clinical use, but it has relatively weak anti-HIV activity and easily induces drug resistance. In succession to T20, T1249 has been designed as a 39-mer peptide composed of amino acid sequences derived from HIV-1, HIV-2, and simian immunodeficiency virus (SIV); however, its development has been suspended due to formulation difficulties. We recently developed a T20-based lipopeptide (LP-40) showing greatly improved pharmaceutical properties. Here, we generated a T1249-based lipopeptide, termed LP-46, by replacing its C-terminal tryptophan-rich sequence with fatty acid. As compared to T20, T1249, and LP-40, the truncated LP-46 (31-mer) had dramatically increased activities in inhibiting a large panel of HIV-1 subtypes, with IC50 values approaching low picomolar (pM) concentrations. Also, LP-46 was an exceptionally potent inhibitor against HIV-2, SIV, and T20-resistant variants, and it displayed obvious synergistic effects with LP-40. Furthermore, we showed that LP-46 had increased helical stability and binding affinity with the target site. The crystal structure of LP-46 in complex with a target surrogate revealed its critical binding motifs underlying the mechanism of action. Interestingly, it was found that the introduced pocket-binding domain (PBD) in LP-46 did not interact with the gp41 pocket as expected; instead, it adopted a mode similar to that of LP-40. Therefore, our studies have provided an exceptionally potent and broad fusion inhibitor for developing new anti-HIV drugs, which can also serve as a tool to exploit the mechanisms of viral fusion and inhibition.

Exceptional Potency and Structural Basis of a T1249-Derived Lipopeptide Fusion Inhibitor against HIV-1, HIV-2, and Simian Immunodeficiency Virus.,Zhu Y, Zhang X, Ding X, Chong H, Cui S, He J, Wang X, He Y J Biol Chem. 2018 Feb 7. pii: RA118.001729. doi: 10.1074/jbc.RA118.001729. PMID:29425101^[1]

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

References

↑ Zhu Y, Zhang X, Ding X, Chong H, Cui S, He J, Wang X, He Y. Exceptional Potency and Structural Basis of a T1249-Derived Lipopeptide Fusion Inhibitor against HIV-1, HIV-2, and Simian Immunodeficiency Virus. J Biol Chem. 2018 Feb 7. pii: RA118.001729. doi: 10.1074/jbc.RA118.001729. PMID:29425101 doi:http://dx.doi.org/10.1074/jbc.RA118.001729

1 Structural highlights
2 Publication Abstract from PubMed
3 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/5yc0"

Categories: Large Structures | He, Y | Wang, X | Zhang, X | 6-hb | Hiv-1 | Viral protein-inhibitor complex

@@ Line 1: / Line 1: @@
 ==Crystal structure of LP-46/N44==
-<StructureSection load='5yc0' size='340' side='right' caption='[[5yc0]], [[Resolution|resolution]] 2.00&Aring;' scene=''>
+<StructureSection load='5yc0' size='340' side='right'caption='[[5yc0]], [[Resolution|resolution]] 2.00&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[5yc0]] is a 12 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5YC0 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5YC0 FirstGlance]. <br>
+<table><tr><td colspan='2'>[[5yc0]] is a 12 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5YC0 OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=5YC0 FirstGlance]. <br>
-</td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5yc0 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5yc0 OCA], [http://pdbe.org/5yc0 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5yc0 RCSB], [http://www.ebi.ac.uk/pdbsum/5yc0 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5yc0 ProSAT]</span></td></tr>
+</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=5yc0 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5yc0 OCA], [http://pdbe.org/5yc0 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5yc0 RCSB], [http://www.ebi.ac.uk/pdbsum/5yc0 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5yc0 ProSAT]</span></td></tr>
 </table>
 <div style="background-color:#fffaf0;">
@@ Line 19: / Line 19: @@
 __TOC__
 </StructureSection>
+[[Category: Large Structures]]
 [[Category: He, Y]]
 [[Category: Wang, X]]

5yc0

From Proteopedia

Revision as of 09:15, 21 October 2020

Crystal structure of LP-46/N44

Structural highlights

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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