View source for 6mvd


==Crystal structure of Lecithin:cholesterol acyltransferase (LCAT) in complex with isopropyl dodec-11-enylfluorophosphonate (IDFP) and a small molecule activator==
<StructureSection load='6mvd' size='340' side='right'caption='[[6mvd]], [[Resolution|resolution]] 3.10&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[6mvd]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. This structure supersedes the now removed PDB entry [http://oca.weizmann.ac.il/oca-bin/send-pdb?obs=1&id=6dtj 6dtj]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6MVD OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6MVD 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]] 3.1&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=H94:6-{4-[(4R)-4-hydroxy-6-oxo-4-(trifluoromethyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-yl]piperidin-1-yl}-4-(trifluoromethyl)pyridine-3-carbonitrile'>H94</scene>, <scene name='pdbligand=H9A:propan-2-yl+hydrogen+(R)-ethylphosphonate'>H9A</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=NI:NICKEL+(II)+ION'>NI</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</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=6mvd FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6mvd OCA], [https://pdbe.org/6mvd PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6mvd RCSB], [https://www.ebi.ac.uk/pdbsum/6mvd PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6mvd ProSAT]</span></td></tr>
</table>
== Disease ==
[https://www.uniprot.org/uniprot/LCAT_HUMAN LCAT_HUMAN] Fish-eye disease;Familial LCAT deficiency. The disease is caused by mutations affecting the gene represented in this entry.  The disease is caused by mutations affecting the gene represented in this entry.
== Function ==
[https://www.uniprot.org/uniprot/LCAT_HUMAN LCAT_HUMAN] Central enzyme in the extracellular metabolism of plasma lipoproteins. Synthesized mainly in the liver and secreted into plasma where it converts cholesterol and phosphatidylcholines (lecithins) to cholesteryl esters and lysophosphatidylcholines on the surface of high and low density lipoproteins (HDLs and LDLs). The cholesterol ester is then transported back to the liver. Has a preference for plasma 16:0-18:2 or 18:O-18:2 phosphatidylcholines. Also produced in the brain by primary astrocytes, and esterifies free cholesterol on nascent APOE-containing lipoproteins secreted from glia and influences cerebral spinal fluid (CSF) APOE- and APOA1 levels. Together with APOE and the cholesterol transporter ABCA1, plays a key role in the maturation of glial-derived, nascent lipoproteins. Required for remodeling high-density lipoprotein particles into their spherical forms.<ref>PMID:10722751</ref> 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Lecithin:cholesterol acyltransferase (LCAT) and LCAT-activating compounds are being investigated as treatments for coronary heart disease (CHD) and familial LCAT deficiency (FLD). Herein we report the crystal structure of human LCAT in complex with a potent piperidinylpyrazolopyridine activator and an acyl intermediate-like inhibitor, revealing LCAT in an active conformation. Unlike other LCAT activators, the piperidinylpyrazolopyridine activator binds exclusively to the membrane-binding domain (MBD). Functional studies indicate that the compound does not modulate the affinity of LCAT for HDL, but instead stabilizes residues in the MBD and facilitates channeling of substrates into the active site. By demonstrating that these activators increase the activity of an FLD variant, we show that compounds targeting the MBD have therapeutic potential. Our data better define the substrate binding site of LCAT and pave the way for rational design of LCAT agonists and improved biotherapeutics for augmenting or restoring reverse cholesterol transport in CHD and FLD patients.

Molecular basis for activation of lecithin:cholesterol acyltransferase by a compound that increases HDL cholesterol.,Manthei KA, Yang SM, Baljinnyam B, Chang L, Glukhova A, Yuan W, Freeman LA, Maloney DJ, Schwendeman A, Remaley AT, Jadhav A, Tesmer JJ Elife. 2018 Nov 27;7. pii: 41604. doi: 10.7554/eLife.41604. PMID:30479275<ref>PMID:30479275</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 6mvd" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Chang L]]
[[Category: Manthei KA]]
[[Category: Tesmer JJG]]