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| | ==Structure of the eukaryotic intramembrane Ras methyltransferase ICMT (isoprenylcysteine carboxyl methyltransferase) without a monobody== | | ==Structure of the eukaryotic intramembrane Ras methyltransferase ICMT (isoprenylcysteine carboxyl methyltransferase) without a monobody== |
| - | <StructureSection load='5vg9' size='340' side='right' caption='[[5vg9]], [[Resolution|resolution]] 4.00Å' scene=''> | + | <StructureSection load='5vg9' size='340' side='right'caption='[[5vg9]], [[Resolution|resolution]] 4.00Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5vg9]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Red_flour_beetle Red flour beetle]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5VG9 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5VG9 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5vg9]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Tribolium_castaneum Tribolium castaneum]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5VG9 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5VG9 FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=SAH:S-ADENOSYL-L-HOMOCYSTEINE'>SAH</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]] 4Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5v7p|5v7p]]</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=SAH:S-ADENOSYL-L-HOMOCYSTEINE'>SAH</scene></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">TcasGA2_TC013078 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=7070 Red flour beetle])</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=5vg9 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5vg9 OCA], [https://pdbe.org/5vg9 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5vg9 RCSB], [https://www.ebi.ac.uk/pdbsum/5vg9 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5vg9 ProSAT]</span></td></tr> |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Protein-S-isoprenylcysteine_O-methyltransferase Protein-S-isoprenylcysteine O-methyltransferase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.1.1.100 2.1.1.100] </span></td></tr>
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| - | <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=5vg9 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5vg9 OCA], [http://pdbe.org/5vg9 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5vg9 RCSB], [http://www.ebi.ac.uk/pdbsum/5vg9 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5vg9 ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| - | <div style="background-color:#fffaf0;">
| + | == Function == |
| - | == Publication Abstract from PubMed == | + | [https://www.uniprot.org/uniprot/ICMT_TRICA ICMT_TRICA] Catalyzes the post-translational methylation of isoprenylated C-terminal cysteine residues.<ref>PMID:29342140</ref> |
| - | The maturation of RAS GTPases and approximately 200 other cellular CAAX proteins involves three enzymatic steps: addition of a farnesyl or geranylgeranyl prenyl lipid to the cysteine (C) in the C-terminal CAAX motif, proteolytic cleavage of the AAX residues and methylation of the exposed prenylcysteine residue at its terminal carboxylate. This final step is catalysed by isoprenylcysteine carboxyl methyltransferase (ICMT), a eukaryote-specific integral membrane enzyme that resides in the endoplasmic reticulum. ICMT is the only cellular enzyme that is known to methylate prenylcysteine substrates; methylation is important for the biological functions of these substrates, such as the membrane localization and subsequent activity of RAS, prelamin A and RAB. Inhibition of ICMT has potential for combating progeria and cancer. Here we present an X-ray structure of ICMT, in complex with its cofactor, an ordered lipid molecule and a monobody inhibitor, at 2.3 A resolution. The active site spans cytosolic and membrane-exposed regions, indicating distinct entry routes for the cytosolic methyl donor, S-adenosyl-l-methionine, and for prenylcysteine substrates, which are associated with the endoplasmic reticulum membrane. The structure suggests how ICMT overcomes the topographical challenge and unfavourable energetics of bringing two reactants that have different cellular localizations together in a membrane environment-a relatively uncharacterized but defining feature of many integral membrane enzymes.
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| - | Atomic structure of the eukaryotic intramembrane RAS methyltransferase ICMT.,Diver MM, Pedi L, Koide A, Koide S, Long SB Nature. 2018 Jan 25;553(7689):526-529. doi: 10.1038/nature25439. Epub 2018 Jan, 17. PMID:29342140<ref>PMID:29342140</ref>
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| - | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
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| - | </div>
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| - | <div class="pdbe-citations 5vg9" style="background-color:#fffaf0;"></div>
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| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Protein-S-isoprenylcysteine O-methyltransferase]] | + | [[Category: Large Structures]] |
| - | [[Category: Red flour beetle]] | + | [[Category: Tribolium castaneum]] |
| - | [[Category: Diver, M M]] | + | [[Category: Diver MM]] |
| - | [[Category: Koide, A]] | + | [[Category: Koide A]] |
| - | [[Category: Koide, S]] | + | [[Category: Koide S]] |
| - | [[Category: Long, S B]] | + | [[Category: Long SB]] |
| - | [[Category: Pedi, L]] | + | [[Category: Pedi L]] |
| - | [[Category: Membrane enzyme]]
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| - | [[Category: Membrane protein]]
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| - | [[Category: Methyltransferase]]
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| - | [[Category: Transferase]]
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