View source for 4msl


==Crystal structure of the Vps10p domain of human sortilin/NTS3 in complex with AF40431==
<StructureSection load='4msl' size='340' side='right'caption='[[4msl]], [[Resolution|resolution]] 2.70&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[4msl]] 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=4MSL OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4MSL 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=2ET:N-[(7-HYDROXY-4-METHYL-2-OXO-2H-CHROMEN-8-YL)METHYL]-L-LEUCINE'>2ET</scene>, <scene name='pdbligand=BMA:BETA-D-MANNOSE'>BMA</scene>, <scene name='pdbligand=MAN:ALPHA-D-MANNOSE'>MAN</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=PG4:TETRAETHYLENE+GLYCOL'>PG4</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=4msl FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4msl OCA], [https://pdbe.org/4msl PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4msl RCSB], [https://www.ebi.ac.uk/pdbsum/4msl PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4msl ProSAT]</span></td></tr>
</table>
== Disease ==
[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 ==
[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;">
== Publication Abstract from PubMed ==
Sortilin is a type I membrane glycoprotein belonging to the vacuolar protein sorting 10 protein (Vps10p) family of sorting receptors and is most abundantly expressed in the central nervous system. Sortilin has emerged as a key player in the regulation of neuronal viability and has been implicated as a possible therapeutic target in a range of disorders. Here, the identification of AF40431, the first reported small-molecule ligand of sortilin, is reported. Crystals of the sortilin-AF40431 complex were obtained by co-crystallization and the structure of the complex was solved to 2.7 A resolution. AF40431 is bound in the neurotensin-binding site of sortilin, with the leucine moiety of AF40431 mimicking the binding mode of the C-terminal leucine of neurotensin and the 4-methylumbelliferone moiety of AF40431 forming pi-stacking with a phenylalanine.

Identification of the first small-molecule ligand of the neuronal receptor sortilin and structure determination of the receptor-ligand complex.,Andersen JL, Schroder TJ, Christensen S, Strandbygard D, Pallesen LT, Garcia-Alai MM, Lindberg S, Langgard M, Eskildsen JC, David L, Tagmose L, Simonsen KB, Maltas PJ, Ronn LC, de Jong IE, Malik IJ, Egebjerg J, Karlsson JJ, Uppalanchi S, Sakumudi DR, Eradi P, Watson SP, Thirup S Acta Crystallogr D Biol Crystallogr. 2014 Feb;70(Pt 2):451-60. doi:, 10.1107/S1399004713030149. Epub 2014 Jan 29. PMID:24531479<ref>PMID:24531479</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 4msl" style="background-color:#fffaf0;"></div>

==See Also==
*[[Neurotensin receptor|Neurotensin receptor]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Andersen JL]]
[[Category: Strandbygaard D]]
[[Category: Thirup S]]