View source for 2xtj


==The crystal structure of PCSK9 in complex with 1D05 Fab==
<StructureSection load='2xtj' size='340' side='right'caption='[[2xtj]], [[Resolution|resolution]] 2.70&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[2xtj]] is a 6 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=2XTJ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2XTJ FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.7&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CA:CALCIUM+ION'>CA</scene></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=2xtj FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2xtj OCA], [https://pdbe.org/2xtj PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2xtj RCSB], [https://www.ebi.ac.uk/pdbsum/2xtj PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2xtj ProSAT]</span></td></tr>
</table>
== Disease ==
[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> 
== Function ==
[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> 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Proprotein convertase subtilisin-like/kexin type 9 regulates LDL cholesterol levels by inhibiting LDL-receptor mediated cellular LDL uptake. We have identified a fragment of antibody (Fab) 1D05 which binds PCSK9 with nanomolar affinity. The fully human antibody 1D05-IgG2 completely blocks the inhibitory effects of wildtype PCSK9 and two gain-of-function human PCSK9 mutants, S127R and D374Y. The crystal structure of 1D05-Fab bound to PCSK9 reveals that 1D05-Fab binds to an epitope on the PCSK9 catalytic domain which includes the entire LDL-receptor EGF(A) binding site. Notably, the 1D05-Fab CDR-H3 and CDR-H2 loops structurally mimic the EGF(A) domain of LDL-receptor. In a transgenic mouse model (CETP/LDL-receptor-hemi) with plasma lipid and PCSK9 profiles comparable to those of humans, 1D05-IgG2 reduces plasma LDL cholesterol 40% and raises hepatic LDL-receptor protein levels approximately five fold. Similarly, in healthy rhesus monkeys, 1D05-IgG2 effectively reduces LDL cholesterol 20-50% for over two weeks, despite its relatively short terminal half life (t1/2=3.2 days). Importantly, the decrease in circulating LDL cholesterol corresponds closely to the reduction in free PCSK9 levels. Together these results clearly demonstrate the LDL-lowering effect of the neutralizing anti-PCSK9 1D05-IgG2 is mediated by reducing the amount of PCSK9 that can bind to the LDL-receptor.

A proprotein convertase subtilisin-like/kexin type 9 (PCSK9)-binding antibody that structurally mimics the EGF(A) domain of LDL-receptor reduces free circulating PCSK9 and LDL-cholesterol.,Ni YG, Di Marco S, Condra JH, Peterson LB, Wang W, Wang F, Pandit S, Hammond HA, Rosa R, Cummings RT, Wood DD, Liu X, Bottomley MJ, Shen X, Cubbon RM, Wang SP, Johns DG, Volpari C, Hamuro L, Chin J, Huang L, Zhao JZ, Vitelli S, Haytko P, Wisniewski D, Mitnaul LJ, Sparrow CP, Hubbard B, Carfi A, Sitlani A J Lipid Res. 2010 Oct 19. PMID:20959675<ref>PMID:20959675</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 2xtj" style="background-color:#fffaf0;"></div>

==See Also==
*[[Monoclonal Antibodies 3D structures|Monoclonal Antibodies 3D structures]]
*[[PCSK9|PCSK9]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Carfi A]]
[[Category: Di Marco S]]
[[Category: Volpari C]]