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==Crystal structure of the Vps10p domain of human sortilin/NTS3 in complex with AF38469==
==Crystal structure of the Vps10p domain of human sortilin/NTS3 in complex with AF38469==
<StructureSection load='4n7e' size='340' side='right' caption='[[4n7e]], [[Resolution|resolution]] 2.70&Aring;' scene=''>
<StructureSection load='4n7e' size='340' side='right'caption='[[4n7e]], [[Resolution|resolution]] 2.70&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>[[4n7e]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4N7E OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4N7E FirstGlance]. <br>
<table><tr><td colspan='2'>[[4n7e]] is a 1 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=4N7E OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4N7E FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=2JQ:2-[(6-METHYLPYRIDIN-2-YL)CARBAMOYL]-5-(TRIFLUOROMETHYL)BENZOIC+ACID'>2JQ</scene>, <scene name='pdbligand=BMA:BETA-D-MANNOSE'>BMA</scene>, <scene name='pdbligand=PGE:TRIETHYLENE+GLYCOL'>PGE</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</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">[[3f6k|3f6k]], [[4msl|4msl]]</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=2JQ:2-[(6-METHYLPYRIDIN-2-YL)CARBAMOYL]-5-(TRIFLUOROMETHYL)BENZOIC+ACID'>2JQ</scene>, <scene name='pdbligand=BMA:BETA-D-MANNOSE'>BMA</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=PGE:TRIETHYLENE+GLYCOL'>PGE</scene></td></tr>
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">SORT1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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=4n7e FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4n7e OCA], [https://pdbe.org/4n7e PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4n7e RCSB], [https://www.ebi.ac.uk/pdbsum/4n7e PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4n7e ProSAT]</span></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=4n7e FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4n7e OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4n7e RCSB], [http://www.ebi.ac.uk/pdbsum/4n7e PDBsum]</span></td></tr>
</table>
</table>
== Disease ==
== Disease ==
[[http://www.uniprot.org/uniprot/SORT_HUMAN SORT_HUMAN]] Note=A common polymorphism located in a non-coding region between CELSR2 and PSRC1 alters a CEBP transcription factor binding site and is responsible for changes in hepatic expression of SORT1. Altered SORT1 expression in liver affects low density lipoprotein cholesterol levels in plasma and is associated with susceptibility to myocardial infarction.  
[https://www.uniprot.org/uniprot/SORT_HUMAN SORT_HUMAN] Note=A common polymorphism located in a non-coding region between CELSR2 and PSRC1 alters a CEBP transcription factor binding site and is responsible for changes in hepatic expression of SORT1. Altered SORT1 expression in liver affects low density lipoprotein cholesterol levels in plasma and is associated with susceptibility to myocardial infarction.
== Function ==
== Function ==
[[http://www.uniprot.org/uniprot/SORT_HUMAN SORT_HUMAN]] Functions as a sorting receptor in the Golgi compartment and as a clearance receptor on the cell surface. Required for protein transport from the Golgi apparatus to the lysosomes by a pathway that is independent of the mannose-6-phosphate receptor (M6PR). Also required for protein transport from the Golgi apparatus to the endosomes. Promotes neuronal apoptosis by mediating endocytosis of the proapoptotic precursor forms of BDNF (proBDNF) and NGFB (proNGFB). Also acts as a receptor for neurotensin. May promote mineralization of the extracellular matrix during osteogenic differentiation by scavenging extracellular LPL. Probably required in adipocytes for the formation of specialized storage vesicles containing the glucose transporter SLC2A4/GLUT4 (GLUT4 storage vesicles, or GSVs). These vesicles provide a stable pool of SLC2A4 and confer increased responsiveness to insulin. May also mediate transport from the endoplasmic reticulum to the Golgi.<ref>PMID:10085125</ref> <ref>PMID:11331584</ref> <ref>PMID:11390366</ref> <ref>PMID:12209882</ref> <ref>PMID:14657016</ref> <ref>PMID:12598608</ref> <ref>PMID:15313463</ref> <ref>PMID:14985763</ref> <ref>PMID:15930396</ref> <ref>PMID:15987945</ref>
[https://www.uniprot.org/uniprot/SORT_HUMAN SORT_HUMAN] Functions as a sorting receptor in the Golgi compartment and as a clearance receptor on the cell surface. Required for protein transport from the Golgi apparatus to the lysosomes by a pathway that is independent of the mannose-6-phosphate receptor (M6PR). Also required for protein transport from the Golgi apparatus to the endosomes. Promotes neuronal apoptosis by mediating endocytosis of the proapoptotic precursor forms of BDNF (proBDNF) and NGFB (proNGFB). Also acts as a receptor for neurotensin. May promote mineralization of the extracellular matrix during osteogenic differentiation by scavenging extracellular LPL. Probably required in adipocytes for the formation of specialized storage vesicles containing the glucose transporter SLC2A4/GLUT4 (GLUT4 storage vesicles, or GSVs). These vesicles provide a stable pool of SLC2A4 and confer increased responsiveness to insulin. May also mediate transport from the endoplasmic reticulum to the Golgi.<ref>PMID:10085125</ref> <ref>PMID:11331584</ref> <ref>PMID:11390366</ref> <ref>PMID:12209882</ref> <ref>PMID:14657016</ref> <ref>PMID:12598608</ref> <ref>PMID:15313463</ref> <ref>PMID:14985763</ref> <ref>PMID:15930396</ref> <ref>PMID:15987945</ref>  
<div style="background-color:#fffaf0;">
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
== Publication Abstract from PubMed ==
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
</div>
<div class="pdbe-citations 4n7e" style="background-color:#fffaf0;"></div>
==See Also==
*[[Neurotensin receptor|Neurotensin receptor]]
== References ==
== References ==
<references/>
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
[[Category: Human]]
[[Category: Homo sapiens]]
[[Category: Andersen, J L]]
[[Category: Large Structures]]
[[Category: Strandbygaard, D]]
[[Category: Andersen JL]]
[[Category: Thirup, S]]
[[Category: Strandbygaard D]]
[[Category: 10cc domain]]
[[Category: Thirup S]]
[[Category: Af38469]]
[[Category: Af40431]]
[[Category: Alzheimer's disease]]
[[Category: Beta-propeller asp-box repeat]]
[[Category: Membrane]]
[[Category: Prongf]]
[[Category: Receptor sorting]]
[[Category: Signaling protein]]
[[Category: Small molecule ligand]]
[[Category: Sortilin]]
[[Category: Vps10p domain]]

Latest revision as of 19:49, 20 September 2023

Crystal structure of the Vps10p domain of human sortilin/NTS3 in complex with AF38469Crystal structure of the Vps10p domain of human sortilin/NTS3 in complex with AF38469

Structural highlights

4n7e is a 1 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

SORT_HUMAN Note=A common polymorphism located in a non-coding region between CELSR2 and PSRC1 alters a CEBP transcription factor binding site and is responsible for changes in hepatic expression of SORT1. Altered SORT1 expression in liver affects low density lipoprotein cholesterol levels in plasma and is associated with susceptibility to myocardial infarction.

Function

SORT_HUMAN Functions as a sorting receptor in the Golgi compartment and as a clearance receptor on the cell surface. Required for protein transport from the Golgi apparatus to the lysosomes by a pathway that is independent of the mannose-6-phosphate receptor (M6PR). Also required for protein transport from the Golgi apparatus to the endosomes. Promotes neuronal apoptosis by mediating endocytosis of the proapoptotic precursor forms of BDNF (proBDNF) and NGFB (proNGFB). Also acts as a receptor for neurotensin. May promote mineralization of the extracellular matrix during osteogenic differentiation by scavenging extracellular LPL. Probably required in adipocytes for the formation of specialized storage vesicles containing the glucose transporter SLC2A4/GLUT4 (GLUT4 storage vesicles, or GSVs). These vesicles provide a stable pool of SLC2A4 and confer increased responsiveness to insulin. May also mediate transport from the endoplasmic reticulum to the Golgi.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10]

Publication Abstract from PubMed

The identification of the novel, selective, orally bioavailable Sortilin inhibitor AF38469 is described. Structure-activity relationships and syntheses are reported, along with an X-ray crystal structure of the sortilin-AF38469 protein-inhibitor complex.

The identification of AF38469: An orally bioavailable inhibitor of the VPS10P family sorting receptor Sortilin.,Schroder TJ, Christensen S, Lindberg S, Langgard M, David L, Maltas PJ, Eskildsen J, Jacobsen J, Tagmose L, Simonsen KB, Biilmann Ronn LC, de Jong IE, Malik IJ, Karlsson JJ, Bundgaard C, Egebjerg J, Stavenhagen JB, Strandbygard D, Thirup S, Andersen JL, Uppalanchi S, Pervaram S, Kasturi SP, Eradi P, Sakumudi DR, Watson SP Bioorg Med Chem Lett. 2014 Jan 1;24(1):177-80. doi: 10.1016/j.bmcl.2013.11.046., Epub 2013 Nov 27. PMID:24355129[11]

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

See Also

References

  1. ↑ Nielsen MS, Jacobsen C, Olivecrona G, Gliemann J, Petersen CM. Sortilin/neurotensin receptor-3 binds and mediates degradation of lipoprotein lipase. J Biol Chem. 1999 Mar 26;274(13):8832-6. PMID:10085125
  2. ↑ Nielsen MS, Madsen P, Christensen EI, Nykjaer A, Gliemann J, Kasper D, Pohlmann R, Petersen CM. The sortilin cytoplasmic tail conveys Golgi-endosome transport and binds the VHS domain of the GGA2 sorting protein. EMBO J. 2001 May 1;20(9):2180-90. PMID:11331584 doi:10.1093/emboj/20.9.2180
  3. ↑ Takatsu H, Katoh Y, Shiba Y, Nakayama K. Golgi-localizing, gamma-adaptin ear homology domain, ADP-ribosylation factor-binding (GGA) proteins interact with acidic dileucine sequences within the cytoplasmic domains of sorting receptors through their Vps27p/Hrs/STAM (VHS) domains. J Biol Chem. 2001 Jul 27;276(30):28541-5. Epub 2001 Jun 4. PMID:11390366 doi:10.1074/jbc.C100218200
  4. ↑ Maeda S, Nobukuni T, Shimo-Onoda K, Hayashi K, Yone K, Komiya S, Inoue I. Sortilin is upregulated during osteoblastic differentiation of mesenchymal stem cells and promotes extracellular matrix mineralization. J Cell Physiol. 2002 Oct;193(1):73-9. PMID:12209882 doi:10.1002/jcp.10151
  5. ↑ Lefrancois S, Zeng J, Hassan AJ, Canuel M, Morales CR. The lysosomal trafficking of sphingolipid activator proteins (SAPs) is mediated by sortilin. EMBO J. 2003 Dec 15;22(24):6430-7. PMID:14657016 doi:10.1093/emboj/cdg629
  6. ↑ Martin S, Vincent JP, Mazella J. Involvement of the neurotensin receptor-3 in the neurotensin-induced migration of human microglia. J Neurosci. 2003 Feb 15;23(4):1198-205. PMID:12598608
  7. ↑ Morinville A, Martin S, Lavallee M, Vincent JP, Beaudet A, Mazella J. Internalization and trafficking of neurotensin via NTS3 receptors in HT29 cells. Int J Biochem Cell Biol. 2004 Nov;36(11):2153-68. PMID:15313463 doi:10.1016/j.biocel.2004.04.013
  8. ↑ Nykjaer A, Lee R, Teng KK, Jansen P, Madsen P, Nielsen MS, Jacobsen C, Kliemannel M, Schwarz E, Willnow TE, Hempstead BL, Petersen CM. Sortilin is essential for proNGF-induced neuronal cell death. Nature. 2004 Feb 26;427(6977):843-8. PMID:14985763 doi:10.1038/nature02319
  9. ↑ Teng HK, Teng KK, Lee R, Wright S, Tevar S, Almeida RD, Kermani P, Torkin R, Chen ZY, Lee FS, Kraemer RT, Nykjaer A, Hempstead BL. ProBDNF induces neuronal apoptosis via activation of a receptor complex of p75NTR and sortilin. J Neurosci. 2005 Jun 1;25(22):5455-63. PMID:15930396 doi:25/22/5455
  10. ↑ Chen ZY, Ieraci A, Teng H, Dall H, Meng CX, Herrera DG, Nykjaer A, Hempstead BL, Lee FS. Sortilin controls intracellular sorting of brain-derived neurotrophic factor to the regulated secretory pathway. J Neurosci. 2005 Jun 29;25(26):6156-66. PMID:15987945 doi:25/26/6156
  11. ↑ Schroder TJ, Christensen S, Lindberg S, Langgard M, David L, Maltas PJ, Eskildsen J, Jacobsen J, Tagmose L, Simonsen KB, Biilmann Ronn LC, de Jong IE, Malik IJ, Karlsson JJ, Bundgaard C, Egebjerg J, Stavenhagen JB, Strandbygard D, Thirup S, Andersen JL, Uppalanchi S, Pervaram S, Kasturi SP, Eradi P, Sakumudi DR, Watson SP. The identification of AF38469: An orally bioavailable inhibitor of the VPS10P family sorting receptor Sortilin. Bioorg Med Chem Lett. 2014 Jan 1;24(1):177-80. doi: 10.1016/j.bmcl.2013.11.046., Epub 2013 Nov 27. PMID:24355129 doi:http://dx.doi.org/10.1016/j.bmcl.2013.11.046

4n7e, resolution 2.70Å

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