3h42

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{{STRUCTURE_3h42| PDB=3h42 | SCENE= }}
 
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===Crystal structure of PCSK9 in complex with Fab from LDLR competitive antibody===
 
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{{ABSTRACT_PUBMED_19443683}}
 
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==Disease==
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==Crystal structure of PCSK9 in complex with Fab from LDLR competitive antibody==
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[[http://www.uniprot.org/uniprot/PCSK9_HUMAN PCSK9_HUMAN]] Defects in PCSK9 are the cause of hypercholesterolemia autosomal dominant type 3 (HCHOLA3) [MIM:[http://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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<StructureSection load='3h42' size='340' side='right'caption='[[3h42]], [[Resolution|resolution]] 2.30&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[3h42]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3H42 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3H42 FirstGlance]. <br>
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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]] 2.3&#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=NA:SODIUM+ION'>NA</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=3h42 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3h42 OCA], [https://pdbe.org/3h42 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3h42 RCSB], [https://www.ebi.ac.uk/pdbsum/3h42 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3h42 ProSAT]</span></td></tr>
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</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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== Evolutionary Conservation ==
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[[Image:Consurf_key_small.gif|200px|right]]
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Check<jmol>
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<jmolCheckbox>
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<scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/h4/3h42_consurf.spt"</scriptWhenChecked>
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<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview03.spt</scriptWhenUnchecked>
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<text>to colour the structure by Evolutionary Conservation</text>
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</jmolCheckbox>
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</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=3h42 ConSurf].
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<div style="clear:both"></div>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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Proprotein convertase subtilisin/kexin type 9 (PCSK9) regulates serum LDL cholesterol (LDL-C) by interacting with the LDL receptor (LDLR) and is an attractive therapeutic target for LDL-C lowering. We have generated a neutralizing anti-PCSK9 antibody, mAb1, that binds to an epitope on PCSK9 adjacent to the region required for LDLR interaction. In vitro, mAb1 inhibits PCSK9 binding to the LDLR and attenuates PCSK9-mediated reduction in LDLR protein levels, thereby increasing LDL uptake. A combination of mAb1 with a statin increases LDLR levels in HepG2 cells more than either treatment alone. In wild-type mice, mAb1 increases hepatic LDLR protein levels approximately 2-fold and lowers total serum cholesterol by up to 36%: this effect is not observed in LDLR(-/-) mice. In cynomolgus monkeys, a single injection of mAb1 reduces serum LDL-C by 80%, and a significant decrease is maintained for 10 days. We conclude that anti-PCSK9 antibodies may be effective therapeutics for treating hypercholesterolemia.
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==Function==
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A proprotein convertase subtilisin/kexin type 9 neutralizing antibody reduces serum cholesterol in mice and nonhuman primates.,Chan JC, Piper DE, Cao Q, Liu D, King C, Wang W, Tang J, Liu Q, Higbee J, Xia Z, Di Y, Shetterly S, Arimura Z, Salomonis H, Romanow WG, Thibault ST, Zhang R, Cao P, Yang XP, Yu T, Lu M, Retter MW, Kwon G, Henne K, Pan O, Tsai MM, Fuchslocher B, Yang E, Zhou L, Lee KJ, Daris M, Sheng J, Wang Y, Shen WD, Yeh WC, Emery M, Walker NP, Shan B, Schwarz M, Jackson SM Proc Natl Acad Sci U S A. 2009 May 14. PMID:19443683<ref>PMID:19443683</ref>
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[[http://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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==About this Structure==
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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[[3h42]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3H42 OCA].
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</div>
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<div class="pdbe-citations 3h42" style="background-color:#fffaf0;"></div>
==See Also==
==See Also==
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*[[Antibody|Antibody]]
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*[[Antibody 3D structures|Antibody 3D structures]]
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*[[PCSK9|PCSK9]]
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==Reference==
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*[[3D structures of human antibody|3D structures of human antibody]]
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<ref group="xtra">PMID:019443683</ref><references group="xtra"/><references/>
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== References ==
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<references/>
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__TOC__
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</StructureSection>
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
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[[Category: Piper, D E.]]
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[[Category: Large Structures]]
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[[Category: Romanow, W G.]]
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[[Category: Piper DE]]
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[[Category: Thibault, S T.]]
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[[Category: Romanow WG]]
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[[Category: Tsai, M M.]]
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[[Category: Thibault ST]]
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[[Category: Walker, N P.C.]]
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[[Category: Tsai MM]]
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[[Category: Yang, E.]]
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[[Category: Walker NPC]]
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[[Category: Autocatalytic cleavage]]
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[[Category: Yang E]]
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[[Category: Cholesterol metabolism]]
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[[Category: Disease mutation]]
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[[Category: Disulfide bond]]
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[[Category: Glycoprotein]]
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[[Category: Hydrolase]]
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[[Category: Hydrolase-immune system complex]]
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[[Category: Lipid metabolism]]
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[[Category: Phosphoprotein]]
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[[Category: Protease]]
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[[Category: Protein fab complex]]
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[[Category: Secreted]]
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[[Category: Serine protease]]
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[[Category: Steroid metabolism]]
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[[Category: Zymogen]]
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Current revision

Crystal structure of PCSK9 in complex with Fab from LDLR competitive antibody

PDB ID 3h42

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