2xtj

From Proteopedia

(Difference between revisions)

Current revision

The crystal structure of PCSK9 in complex with 1D05 Fab

Structural highlights

2xtj is a 6 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.7Å
Ligands:
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

PCSK9_HUMAN Defects in PCSK9 are the cause of hypercholesterolemia autosomal dominant type 3 (HCHOLA3) [MIM:603776. A familial condition characterized by elevated circulating cholesterol contained in either low-density lipoproteins alone or also in very-low-density lipoproteins.^[1]

Function

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.^[2] ^[3] ^[4] ^[5] ^[6] ^[7] ^[8]

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^[9]

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

References

↑ Abifadel M, Varret M, Rabes JP, Allard D, Ouguerram K, Devillers M, Cruaud C, Benjannet S, Wickham L, Erlich D, Derre A, Villeger L, Farnier M, Beucler I, Bruckert E, Chambaz J, Chanu B, Lecerf JM, Luc G, Moulin P, Weissenbach J, Prat A, Krempf M, Junien C, Seidah NG, Boileau C. Mutations in PCSK9 cause autosomal dominant hypercholesterolemia. Nat Genet. 2003 Jun;34(2):154-6. PMID:12730697 doi:10.1038/ng1161
↑ Nassoury N, Blasiole DA, Tebon Oler A, Benjannet S, Hamelin J, Poupon V, McPherson PS, Attie AD, Prat A, Seidah NG. The cellular trafficking of the secretory proprotein convertase PCSK9 and its dependence on the LDLR. Traffic. 2007 Jun;8(6):718-32. Epub 2007 Apr 25. PMID:17461796 doi:10.1111/j.1600-0854.2007.00562.x
↑ Fan D, Yancey PG, Qiu S, Ding L, Weeber EJ, Linton MF, Fazio S. Self-association of human PCSK9 correlates with its LDLR-degrading activity. Biochemistry. 2008 Feb 12;47(6):1631-9. doi: 10.1021/bi7016359. Epub 2008 Jan 16. PMID:18197702 doi:10.1021/bi7016359
↑ Jonas MC, Costantini C, Puglielli L. PCSK9 is required for the disposal of non-acetylated intermediates of the nascent membrane protein BACE1. EMBO Rep. 2008 Sep;9(9):916-22. doi: 10.1038/embor.2008.132. Epub 2008 Jul 25. PMID:18660751 doi:10.1038/embor.2008.132
↑ Poirier S, Mayer G, Benjannet S, Bergeron E, Marcinkiewicz J, Nassoury N, Mayer H, Nimpf J, Prat A, Seidah NG. The proprotein convertase PCSK9 induces the degradation of low density lipoprotein receptor (LDLR) and its closest family members VLDLR and ApoER2. J Biol Chem. 2008 Jan 25;283(4):2363-72. Epub 2007 Nov 26. PMID:18039658 doi:10.1074/jbc.M708098200
↑ Chen Y, Wang H, Yu L, Yu X, Qian YW, Cao G, Wang J. Role of ubiquitination in PCSK9-mediated low-density lipoprotein receptor degradation. Biochem Biophys Res Commun. 2011 Nov 25;415(3):515-8. doi:, 10.1016/j.bbrc.2011.10.110. Epub 2011 Nov 2. PMID:22074827 doi:10.1016/j.bbrc.2011.10.110
↑ Sun H, Samarghandi A, Zhang N, Yao Z, Xiong M, Teng BB. Proprotein convertase subtilisin/kexin type 9 interacts with apolipoprotein B and prevents its intracellular degradation, irrespective of the low-density lipoprotein receptor. Arterioscler Thromb Vasc Biol. 2012 Jul;32(7):1585-95. doi:, 10.1161/ATVBAHA.112.250043. Epub 2012 May 10. PMID:22580899 doi:10.1161/ATVBAHA.112.250043
↑ Sharotri V, Collier DM, Olson DR, Zhou R, Snyder PM. Regulation of epithelial sodium channel trafficking by proprotein convertase subtilisin/kexin type 9 (PCSK9). J Biol Chem. 2012 Jun 1;287(23):19266-74. doi: 10.1074/jbc.M112.363382. Epub 2012, Apr 9. PMID:22493497 doi:10.1074/jbc.M112.363382
↑ 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. 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. J Lipid Res. 2010 Oct 19. PMID:20959675 doi:10.1194/jlr.M011445

1 Structural highlights
2 Disease
3 Function
4 Publication Abstract from PubMed
5 See Also
6 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/2xtj"

Categories: Homo sapiens | Large Structures | Carfi A | Di Marco S | Volpari C

@@ Line 1: / Line 1: @@
-==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=''>
+==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 [http://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 [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2XTJ FirstGlance]. <br>
+<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='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CA:CALCIUM+ION'>CA</scene></td></tr>
+</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='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[2w2n|2w2n]], [[2w2p|2w2p]], [[2w2m|2w2m]], [[2w2o|2w2o]], [[2w2q|2w2q]]</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'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2xtj FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2xtj OCA], [http://www.rcsb.org/pdb/explore.do?structureId=2xtj RCSB], [http://www.ebi.ac.uk/pdbsum/2xtj PDBsum]</span></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 ==
-[[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>
+[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 ==
-[[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>
+[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 ==
@@ Line 19: / Line 20: @@
 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 Antibody|Monoclonal Antibody]]
+*[[Monoclonal Antibodies 3D structures|Monoclonal Antibodies 3D structures]]
 *[[PCSK9|PCSK9]]
 == References ==
@@ Line 28: / Line 30: @@
 </StructureSection>
 [[Category: Homo sapiens]]
-[[Category: Carfi, A]]
+[[Category: Large Structures]]
-[[Category: Marco, S Di]]
+[[Category: Carfi A]]
-[[Category: Volpari, C]]
+[[Category: Di Marco S]]
-[[Category: Egf-a]]
+[[Category: Volpari C]]
-[[Category: Hydrolase-antibody complex]]
-[[Category: Hypercholesterolemia]]
-[[Category: Ldl-c]]
-[[Category: Ldlr]]
-[[Category: Serine protease]]

2xtj

From Proteopedia

Current revision

The crystal structure of PCSK9 in complex with 1D05 Fab

Structural highlights

Disease

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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