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| | <StructureSection load='5bv7' size='340' side='right'caption='[[5bv7]], [[Resolution|resolution]] 2.45Å' scene=''> | | <StructureSection load='5bv7' size='340' side='right'caption='[[5bv7]], [[Resolution|resolution]] 2.45Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5bv7]] is a 5 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human] and [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5BV7 OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=5BV7 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5bv7]] is a 5 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=5BV7 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5BV7 FirstGlance]. <br> |
| | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=MAN:ALPHA-D-MANNOSE'>MAN</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene></td></tr> | | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=MAN:ALPHA-D-MANNOSE'>MAN</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene></td></tr> |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Phosphatidylcholine--sterol_O-acyltransferase Phosphatidylcholine--sterol O-acyltransferase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.3.1.43 2.3.1.43] </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=5bv7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5bv7 OCA], [https://pdbe.org/5bv7 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5bv7 RCSB], [https://www.ebi.ac.uk/pdbsum/5bv7 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5bv7 ProSAT]</span></td></tr> |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=5bv7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5bv7 OCA], [http://pdbe.org/5bv7 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5bv7 RCSB], [http://www.ebi.ac.uk/pdbsum/5bv7 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5bv7 ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Disease == | | == Disease == |
| - | [[http://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. | + | [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 == | | == Function == |
| - | [[http://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> | + | [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;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | </StructureSection> | | </StructureSection> |
| | [[Category: Homo sapiens]] | | [[Category: Homo sapiens]] |
| - | [[Category: Human]] | |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Phosphatidylcholine--sterol O-acyltransferase]]
| + | [[Category: Piper DE]] |
| - | [[Category: Piper, D E]] | + | [[Category: Romanow WG]] |
| - | [[Category: Romanow, W G]] | + | [[Category: Thibault ST]] |
| - | [[Category: Thibault, S T]] | + | [[Category: Walker NPC]] |
| - | [[Category: Walker, N P.C]] | + | |
| - | [[Category: A/b hydrolase]]
| + | |
| - | [[Category: Hydrolase-immune system complex]]
| + | |
| - | [[Category: Immune system]]
| + | |
| Structural highlights
Disease
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
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.[1]
Publication Abstract from PubMed
Drug discovery opportunities where loss-of-function alleles of a target gene link to a disease-relevant phenotype often require an agonism approach to up-regulate or re-establish the activity of the target gene. Antibody therapy is increasingly recognized as a favored drug modality due to multiple desirable pharmacological properties. However, agonistic antibodies that enhance the activities of the target enzymes are rarely developed since the discovery of agonistic antibodies remains elusive. Here we report an innovative scheme of discovery and characterization of human antibodies capable of binding to and agonizing a circulating enzyme lecithin cholesterol acyltransferase (LCAT). Utilizing a modified human LCAT protein with enhanced enzymatic activity as an immunogen, we generated fully human monoclonal antibodies using the XenoMouseTM platform. One of the resultant agonistic antibodies, 27C3, binds to and substantially enhances the activity of LCAT from humans and cynomolgus macaques. X-ray crystallographic analysis of the 2.45 A LCAT/27C3 complex shows that 27C3 binding does not induce notable structural changes in LCAT. A single administration of 27C3 to cynomolgus monkeys led to a rapid increase of plasma LCAT enzymatic activity and a 35 % increase of the high density lipoprotein cholesterol that was observed up to 32 days post 27C3 administration. Thus, this novel scheme of immunization in conjunction with high throughput screening may represent an effective strategy for discovering agonistic antibodies against other enzyme targets. 27C3 and other agonistic human anti-human LCAT monoclonal antibodies described herein hold potential for therapeutic development for the treatment of dyslipidemia and cardiovascular disease.
Agonistic Human Antibodies Binding To Lecithin-Cholesterol Acyltransferase Modulate High Density Lipoprotein Metabolism.,Gunawardane RN, Fordstrom P, Piper DE, Masterman S, Siu S, Liu D, Brown M, Lu M, Tang J, Zhang R, Cheng J, Gates A, Meininger D, Chan J, Carlson T, Walker N, Schwarz M, Delaney J, Zhou M J Biol Chem. 2015 Dec 7. pii: jbc.M115.672790. PMID:26644477[2]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Clay MA, Pyle DH, Rye KA, Barter PJ. Formation of spherical, reconstituted high density lipoproteins containing both apolipoproteins A-I and A-II is mediated by lecithin:cholesterol acyltransferase. J Biol Chem. 2000 Mar 24;275(12):9019-25. PMID:10722751
- ↑ Gunawardane RN, Fordstrom P, Piper DE, Masterman S, Siu S, Liu D, Brown M, Lu M, Tang J, Zhang R, Cheng J, Gates A, Meininger D, Chan J, Carlson T, Walker N, Schwarz M, Delaney J, Zhou M. Agonistic Human Antibodies Binding To Lecithin-Cholesterol Acyltransferase Modulate High Density Lipoprotein Metabolism. J Biol Chem. 2015 Dec 7. pii: jbc.M115.672790. PMID:26644477 doi:http://dx.doi.org/10.1074/jbc.M115.672790
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