7s5h

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==PCSK9(deltaCRD) in complex with cyclic peptide 35==
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<StructureSection load='7s5h' size='340' side='right'caption='[[7s5h]]' scene=''>
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<StructureSection load='7s5h' size='340' side='right'caption='[[7s5h]], [[Resolution|resolution]] 1.27&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id= OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol= FirstGlance]. <br>
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<table><tr><td colspan='2'>[[7s5h]] is a 3 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] 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=7S5H OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7S5H FirstGlance]. <br>
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</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=7s5h FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7s5h OCA], [https://pdbe.org/7s5h PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7s5h RCSB], [https://www.ebi.ac.uk/pdbsum/7s5h PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7s5h ProSAT]</span></td></tr>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.272&#8491;</td></tr>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=0A1:O-METHYL-L-TYROSINE'>0A1</scene>, <scene name='pdbligand=3WX:2-METHYL-L-PROLINE'>3WX</scene>, <scene name='pdbligand=89N:(2E)-but-2-ene-1,4-diol'>89N</scene>, <scene name='pdbligand=8DN:1-(3,5-dimethylphenyl)-4-methyl-1H-1,2,3-triazole'>8DN</scene>, <scene name='pdbligand=DAL:D-ALANINE'>DAL</scene>, <scene name='pdbligand=DHL:2-AMINO-ETHANETHIOL'>DHL</scene>, <scene name='pdbligand=DNP:3-AMINO-ALANINE'>DNP</scene>, <scene name='pdbligand=FTR:FLUOROTRYPTOPHANE'>FTR</scene>, <scene name='pdbligand=MPT:BETA-MERCAPTOPROPIONIC+ACID'>MPT</scene></td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=7s5h FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7s5h OCA], [https://pdbe.org/7s5h PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7s5h RCSB], [https://www.ebi.ac.uk/pdbsum/7s5h PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7s5h ProSAT]</span></td></tr>
</table>
</table>
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== Disease ==
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[https://www.uniprot.org/uniprot/PCSK9_HUMAN PCSK9_HUMAN] Defects in PCSK9 are the cause of hypercholesterolemia autosomal dominant type 3 (HCHOLA3) [MIM:[https://omim.org/entry/603776 603776]. A familial condition characterized by elevated circulating cholesterol contained in either low-density lipoproteins alone or also in very-low-density lipoproteins.<ref>PMID:12730697</ref>
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== Function ==
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[https://www.uniprot.org/uniprot/PCSK9_HUMAN PCSK9_HUMAN] Crucial player in the regulation of plasma cholesterol homeostasis. Binds to low-density lipid receptor family members: low density lipoprotein receptor (LDLR), very low density lipoprotein receptor (VLDLR), apolipoprotein E receptor (LRP1/APOER) and apolipoprotein receptor 2 (LRP8/APOER2), and promotes their degradation in intracellular acidic compartments. Acts via a non-proteolytic mechanism to enhance the degradation of the hepatic LDLR through a clathrin LDLRAP1/ARH-mediated pathway. May prevent the recycling of LDLR from endosomes to the cell surface or direct it to lysosomes for degradation. Can induce ubiquitination of LDLR leading to its subsequent degradation. Inhibits intracellular degradation of APOB via the autophagosome/lysosome pathway in a LDLR-independent manner. Involved in the disposal of non-acetylated intermediates of BACE1 in the early secretory pathway. Inhibits epithelial Na(+) channel (ENaC)-mediated Na(+) absorption by reducing ENaC surface expression primarily by increasing its proteasomal degradation. Regulates neuronal apoptosis via modulation of LRP8/APOER2 levels and related anti-apoptotic signaling pathways.<ref>PMID:17461796</ref> <ref>PMID:18197702</ref> <ref>PMID:18660751</ref> <ref>PMID:18039658</ref> <ref>PMID:22074827</ref> <ref>PMID:22580899</ref> <ref>PMID:22493497</ref>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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Proprotein convertase subtilisin-like/kexin type 9 (PCSK9) is a key regulator of plasma LDL-cholesterol (LDL-C) and a clinically validated target for the treatment of hypercholesterolemia and coronary artery disease. Starting from second-generation lead structures such as 2, we were able to refine these structures to obtain extremely potent bi- and tricyclic PCSK9 inhibitor peptides. Optimized molecules such as 44 demonstrated sufficient oral bioavailability to maintain therapeutic levels in rats and cynomolgus monkeys after dosing with an enabled formulation. We demonstrated target engagement and LDL lowering in cynomolgus monkeys essentially identical to those observed with the clinically approved, parenterally dosed antibodies. These molecules represent the first report of highly potent and orally bioavailable macrocyclic peptide PCSK9 inhibitors with overall profiles favorable for potential development as once-daily oral lipid-lowering agents. In this manuscript, we detail the design criteria and multiparameter optimization of this novel series of PCSK9 inhibitors.
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A Series of Novel, Highly Potent, and Orally Bioavailable Next-Generation Tricyclic Peptide PCSK9 Inhibitors.,Tucker TJ, Embrey MW, Alleyne C, Amin RP, Bass A, Bhatt B, Bianchi E, Branca D, Bueters T, Buist N, Ha SN, Hafey M, He H, Higgins J, Johns DG, Kerekes AD, Koeplinger KA, Kuethe JT, Li N, Murphy B, Orth P, Salowe S, Shahripour A, Tracy R, Wang W, Wu C, Xiong Y, Zokian HJ, Wood HB, Walji A J Med Chem. 2021 Nov 25;64(22):16770-16800. doi: 10.1021/acs.jmedchem.1c01599. , Epub 2021 Oct 27. PMID:34704436<ref>PMID:34704436</ref>
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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</div>
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<div class="pdbe-citations 7s5h" style="background-color:#fffaf0;"></div>
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==See Also==
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*[[PCSK9|PCSK9]]
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== References ==
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<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
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[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Large Structures]]
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[[Category: Z-disk]]
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[[Category: Synthetic construct]]
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[[Category: Orth P]]

Current revision

PCSK9(deltaCRD) in complex with cyclic peptide 35

PDB ID 7s5h

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