6u2f: Difference between revisions
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<StructureSection load='6u2f' size='340' side='right'caption='[[6u2f]], [[Resolution|resolution]] 2.94Å' scene=''> | <StructureSection load='6u2f' size='340' side='right'caption='[[6u2f]], [[Resolution|resolution]] 2.94Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[6u2f]] is a 4 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6U2F OCA]. For a <b>guided tour on the structure components</b> use [ | <table><tr><td colspan='2'>[[6u2f]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens], [https://en.wikipedia.org/wiki/Mus_musculus Mus musculus] and [https://en.wikipedia.org/wiki/Synthetic_construct Synthetic construct]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6U2F OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6U2F FirstGlance]. <br> | ||
</td></tr><tr id=' | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.94Å</td></tr> | ||
<tr id=' | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=HRG:L-HOMOARGININE'>HRG</scene>, <scene name='pdbligand=PQG:cis-1-amino-4-phenylcyclohexane-1-carboxylic+acid'>PQG</scene></td></tr> | ||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[ | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=6u2f FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6u2f OCA], [https://pdbe.org/6u2f PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6u2f RCSB], [https://www.ebi.ac.uk/pdbsum/6u2f PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6u2f ProSAT]</span></td></tr> | ||
</table> | </table> | ||
== Function == | == Function == | ||
[ | [https://www.uniprot.org/uniprot/A0A0U5BC76_MOUSE A0A0U5BC76_MOUSE] | ||
<div style="background-color:#fffaf0;"> | <div style="background-color:#fffaf0;"> | ||
== Publication Abstract from PubMed == | == Publication Abstract from PubMed == | ||
| Line 21: | Line 19: | ||
</div> | </div> | ||
<div class="pdbe-citations 6u2f" style="background-color:#fffaf0;"></div> | <div class="pdbe-citations 6u2f" style="background-color:#fffaf0;"></div> | ||
==See Also== | |||
*[[PCSK9|PCSK9]] | |||
== References == | == References == | ||
<references/> | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Homo sapiens]] | |||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: | [[Category: Mus musculus]] | ||
[[Category: | [[Category: Synthetic construct]] | ||
[[Category: | [[Category: Kirchhofer D]] | ||
[[Category: | [[Category: Ultsch MH]] | ||
Latest revision as of 10:42, 11 October 2023
PCSK9-Fab 7G7 complex bound to cis-1-amino-4-phenylcyclohexaneacyl-WNLK(hR)IGLLR - NH2PCSK9-Fab 7G7 complex bound to cis-1-amino-4-phenylcyclohexaneacyl-WNLK(hR)IGLLR - NH2
Structural highlights
FunctionPublication Abstract from PubMedProprotein convertase subtilisin/kexin 9 (PCSK9) has become an important therapeutic target for lipid lowering, since it regulates low-density lipoprotein cholesterol (LDL-c) levels by binding to liver LDL receptors (LDLR) and effecting their intracellular degradation. However, the development of small molecule inhibitors is hampered by the lack of attractive PCSK9 target sites. We recently discovered helical peptides that are able to bind to a cryptic groove site on PCSK9, which is situated in proximity to the main LDLR binding site. Here, we designed potent bipartite PCSK9 inhibitors by appending organic moieties to a helical groove-binding peptide to reach a hydrophobic pocket in the proximal LDLR binding region. The ultimately designed 1-amino-4-phenylcyclohexane-1-carbonyl extension improved the peptide affinity by >100-fold, yielding organo-peptide antagonists that potently inhibited PCSK9 binding to LDLR and preserved cellular LDLR. These new bipartite antagonists have reduced mass and improved potency compared to the first-generation peptide antagonists, further validating the PCSK9 groove as a viable therapeutic target site. Design of Organo-Peptides As Bipartite PCSK9 Antagonists.,Burdick DJ, Skelton NJ, Ultsch M, Beresini MH, Eigenbrot C, Li W, Zhang Y, Nguyen H, Kong-Beltran M, Quinn JG, Kirchhofer D ACS Chem Biol. 2020 Jan 30. doi: 10.1021/acschembio.9b00899. PMID:31962046[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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