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| - | [[Image:2can.gif|left|200px]] | |
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| - | {{Structure
| + | ==HUMAN ORNITHINE AMINOTRANSFERASE COMPLEXED WITH L-CANALINE== |
| - | |PDB= 2can |SIZE=350|CAPTION= <scene name='initialview01'>2can</scene>, resolution 2.30Å
| + | <StructureSection load='2can' size='340' side='right'caption='[[2can]], [[Resolution|resolution]] 2.30Å' scene=''> |
| - | |SITE=
| + | == Structural highlights == |
| - | |LIGAND= <scene name='pdbligand=CAN:CANALINE'>CAN</scene>, <scene name='pdbligand=PLP:PYRIDOXAL-5'-PHOSPHATE'>PLP</scene> | + | <table><tr><td colspan='2'>[[2can]] is a 3 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=2CAN OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2CAN FirstGlance]. <br> |
| - | |ACTIVITY= <span class='plainlinks'>[http://en.wikipedia.org/wiki/Ornithine_aminotransferase Ornithine aminotransferase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.6.1.13 2.6.1.13] </span>
| + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.3Å</td></tr> |
| - | |GENE=
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CAN:CANALINE'>CAN</scene>, <scene name='pdbligand=PLP:PYRIDOXAL-5-PHOSPHATE'>PLP</scene></td></tr> |
| - | |DOMAIN=
| + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=2can FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2can OCA], [https://pdbe.org/2can PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2can RCSB], [https://www.ebi.ac.uk/pdbsum/2can PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2can ProSAT]</span></td></tr> |
| - | |RELATEDENTRY=
| + | </table> |
| - | |RESOURCES=<span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2can FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2can OCA], [http://www.ebi.ac.uk/pdbsum/2can PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=2can RCSB]</span>
| + | == Disease == |
| - | }}
| + | [https://www.uniprot.org/uniprot/OAT_HUMAN OAT_HUMAN] Defects in OAT are the cause of hyperornithinemia with gyrate atrophy of choroid and retina (HOGA) [MIM:[https://omim.org/entry/258870 258870]. HOGA is a slowly progressive blinding autosomal recessive disorder.<ref>PMID:3375240</ref> <ref>PMID:2793865</ref> <ref>PMID:1612597</ref> <ref>PMID:1737786</ref> <ref>PMID:7887415</ref> <ref>PMID:7668253</ref> |
| | + | == Function == |
| | + | [https://www.uniprot.org/uniprot/OAT_HUMAN OAT_HUMAN] |
| | + | == Evolutionary Conservation == |
| | + | [[Image:Consurf_key_small.gif|200px|right]] |
| | + | Check<jmol> |
| | + | <jmolCheckbox> |
| | + | <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/ca/2can_consurf.spt"</scriptWhenChecked> |
| | + | <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked> |
| | + | <text>to colour the structure by Evolutionary Conservation</text> |
| | + | </jmolCheckbox> |
| | + | </jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=2can ConSurf]. |
| | + | <div style="clear:both"></div> |
| | + | <div style="background-color:#fffaf0;"> |
| | + | == Publication Abstract from PubMed == |
| | + | BACKGROUND: Ornithine aminotransferase (OAT) is a 45 kDa pyridoxal-5'-phosphate (PLP)-dependent enzyme that catalyzes the conversion of L-ornithine and 2-oxoglutarate to glutamate-delta-semialdehyde and glutamic acid, respectively. In humans, loss of OAT function causes an accumulation of ornithine that results in gyrate atrophy of the choroid and retina, a disease that progressively leads to blindness. In an effort to learn more about the structural basis of this enzyme's function, we have determined the X-ray structures of OAT in complex with two enzyme-activated suicide substrates: L-canaline, an ornithine analog, and gabaculine, an irreversible inhibitor of several related aminotransferases. RESULTS: The structures of human OAT bound to the inhibitors gabaculine and L-canaline were solved to 2.3 A at 110K by difference Fourier techniques. Both inhibitors coordinate similarly in the active site, binding covalently to the PLP cofactor and causing a 20 degrees rotation in the cofactor tilt relative to the ligand-free form. Aromatic-aromatic interactions occur between the bound gabaculine molecule and active-site residues Tyr85 and Phe177, whereas Tyr55 and Arg180 provide specific contacts to the alpha-amino and carboxyl groups of L-canaline. CONCLUSIONS: The OAT-L-canaline complex structure implicates Tyr55 and Arg180 as the residues involved in coordinating with the natural substrate ornithine during normal enzyme turnover. This correlates well with two enzyme-inactivating point mutations associated with gyrate atrophy, Tyr55-->His and Arg180-->Thr. The OAT-gabaculine complex provides the first structural evidence that the potency of the inhibitor is due to energetically favourable aromatic interactions with residues in the active site. This aromatic-binding mode may be relevant to structure-based drug design efforts against other omega-aminotransferase targets, such as GABA aminotransferase. |
| | | | |
| - | '''HUMAN ORNITHINE AMINOTRANSFERASE COMPLEXED WITH L-CANALINE'''
| + | Human ornithine aminotransferase complexed with L-canaline and gabaculine: structural basis for substrate recognition.,Shah SA, Shen BW, Brunger AT Structure. 1997 Aug 15;5(8):1067-75. PMID:9309222<ref>PMID:9309222</ref> |
| | | | |
| | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> |
| | + | </div> |
| | + | <div class="pdbe-citations 2can" style="background-color:#fffaf0;"></div> |
| | | | |
| - | ==Overview== | + | ==See Also== |
| - | BACKGROUND: Ornithine aminotransferase (OAT) is a 45 kDa pyridoxal-5'-phosphate (PLP)-dependent enzyme that catalyzes the conversion of L-ornithine and 2-oxoglutarate to glutamate-delta-semialdehyde and glutamic acid, respectively. In humans, loss of OAT function causes an accumulation of ornithine that results in gyrate atrophy of the choroid and retina, a disease that progressively leads to blindness. In an effort to learn more about the structural basis of this enzyme's function, we have determined the X-ray structures of OAT in complex with two enzyme-activated suicide substrates: L-canaline, an ornithine analog, and gabaculine, an irreversible inhibitor of several related aminotransferases. RESULTS: The structures of human OAT bound to the inhibitors gabaculine and L-canaline were solved to 2.3 A at 110K by difference Fourier techniques. Both inhibitors coordinate similarly in the active site, binding covalently to the PLP cofactor and causing a 20 degrees rotation in the cofactor tilt relative to the ligand-free form. Aromatic-aromatic interactions occur between the bound gabaculine molecule and active-site residues Tyr85 and Phe177, whereas Tyr55 and Arg180 provide specific contacts to the alpha-amino and carboxyl groups of L-canaline. CONCLUSIONS: The OAT-L-canaline complex structure implicates Tyr55 and Arg180 as the residues involved in coordinating with the natural substrate ornithine during normal enzyme turnover. This correlates well with two enzyme-inactivating point mutations associated with gyrate atrophy, Tyr55-->His and Arg180-->Thr. The OAT-gabaculine complex provides the first structural evidence that the potency of the inhibitor is due to energetically favourable aromatic interactions with residues in the active site. This aromatic-binding mode may be relevant to structure-based drug design efforts against other omega-aminotransferase targets, such as GABA aminotransferase.
| + | *[[Aminotransferase 3D structures|Aminotransferase 3D structures]] |
| - | | + | == References == |
| - | ==About this Structure== | + | <references/> |
| - | 2CAN is a [[Single protein]] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2CAN OCA].
| + | __TOC__ |
| - | | + | </StructureSection> |
| - | ==Reference==
| + | |
| - | Human ornithine aminotransferase complexed with L-canaline and gabaculine: structural basis for substrate recognition., Shah SA, Shen BW, Brunger AT, Structure. 1997 Aug 15;5(8):1067-75. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/9309222 9309222]
| + | |
| | [[Category: Homo sapiens]] | | [[Category: Homo sapiens]] |
| - | [[Category: Ornithine aminotransferase]] | + | [[Category: Large Structures]] |
| - | [[Category: Single protein]]
| + | [[Category: Brunger AT]] |
| - | [[Category: Brunger, A T.]] | + | [[Category: Shah SA]] |
| - | [[Category: Shah, S A.]] | + | [[Category: Shen BW]] |
| - | [[Category: Shen, B W.]] | + | |
| - | [[Category: ornithine aminotransferase]]
| + | |
| - | [[Category: pyridoxal-5'-phosphate]]
| + | |
| - | [[Category: transferase]]
| + | |
| - | [[Category: urea cycle]]
| + | |
| - | | + | |
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Mar 31 02:18:49 2008''
| + | |
| Structural highlights
Disease
OAT_HUMAN Defects in OAT are the cause of hyperornithinemia with gyrate atrophy of choroid and retina (HOGA) [MIM:258870. HOGA is a slowly progressive blinding autosomal recessive disorder.[1] [2] [3] [4] [5] [6]
Function
OAT_HUMAN
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
BACKGROUND: Ornithine aminotransferase (OAT) is a 45 kDa pyridoxal-5'-phosphate (PLP)-dependent enzyme that catalyzes the conversion of L-ornithine and 2-oxoglutarate to glutamate-delta-semialdehyde and glutamic acid, respectively. In humans, loss of OAT function causes an accumulation of ornithine that results in gyrate atrophy of the choroid and retina, a disease that progressively leads to blindness. In an effort to learn more about the structural basis of this enzyme's function, we have determined the X-ray structures of OAT in complex with two enzyme-activated suicide substrates: L-canaline, an ornithine analog, and gabaculine, an irreversible inhibitor of several related aminotransferases. RESULTS: The structures of human OAT bound to the inhibitors gabaculine and L-canaline were solved to 2.3 A at 110K by difference Fourier techniques. Both inhibitors coordinate similarly in the active site, binding covalently to the PLP cofactor and causing a 20 degrees rotation in the cofactor tilt relative to the ligand-free form. Aromatic-aromatic interactions occur between the bound gabaculine molecule and active-site residues Tyr85 and Phe177, whereas Tyr55 and Arg180 provide specific contacts to the alpha-amino and carboxyl groups of L-canaline. CONCLUSIONS: The OAT-L-canaline complex structure implicates Tyr55 and Arg180 as the residues involved in coordinating with the natural substrate ornithine during normal enzyme turnover. This correlates well with two enzyme-inactivating point mutations associated with gyrate atrophy, Tyr55-->His and Arg180-->Thr. The OAT-gabaculine complex provides the first structural evidence that the potency of the inhibitor is due to energetically favourable aromatic interactions with residues in the active site. This aromatic-binding mode may be relevant to structure-based drug design efforts against other omega-aminotransferase targets, such as GABA aminotransferase.
Human ornithine aminotransferase complexed with L-canaline and gabaculine: structural basis for substrate recognition.,Shah SA, Shen BW, Brunger AT Structure. 1997 Aug 15;5(8):1067-75. PMID:9309222[7]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Ramesh V, McClatchey AI, Ramesh N, Benoit LA, Berson EL, Shih VE, Gusella JF. Molecular basis of ornithine aminotransferase deficiency in B-6-responsive and -nonresponsive forms of gyrate atrophy. Proc Natl Acad Sci U S A. 1988 Jun;85(11):3777-80. PMID:3375240
- ↑ Inana G, Chambers C, Hotta Y, Inouye L, Filpula D, Pulford S, Shiono T. Point mutation affecting processing of the ornithine aminotransferase precursor protein in gyrate atrophy. J Biol Chem. 1989 Oct 15;264(29):17432-6. PMID:2793865
- ↑ Michaud J, Brody LC, Steel G, Fontaine G, Martin LS, Valle D, Mitchell G. Strand-separating conformational polymorphism analysis: efficacy of detection of point mutations in the human ornithine delta-aminotransferase gene. Genomics. 1992 Jun;13(2):389-94. PMID:1612597
- ↑ Brody LC, Mitchell GA, Obie C, Michaud J, Steel G, Fontaine G, Robert MF, Sipila I, Kaiser-Kupfer M, Valle D. Ornithine delta-aminotransferase mutations in gyrate atrophy. Allelic heterogeneity and functional consequences. J Biol Chem. 1992 Feb 15;267(5):3302-7. PMID:1737786
- ↑ Michaud J, Thompson GN, Brody LC, Steel G, Obie C, Fontaine G, Schappert K, Keith CG, Valle D, Mitchell GA. Pyridoxine-responsive gyrate atrophy of the choroid and retina: clinical and biochemical correlates of the mutation A226V. Am J Hum Genet. 1995 Mar;56(3):616-22. PMID:7887415
- ↑ Kobayashi T, Ogawa H, Kasahara M, Shiozawa Z, Matsuzawa T. A single amino acid substitution within the mature sequence of ornithine aminotransferase obstructs mitochondrial entry of the precursor. Am J Hum Genet. 1995 Aug;57(2):284-91. PMID:7668253
- ↑ Shah SA, Shen BW, Brunger AT. Human ornithine aminotransferase complexed with L-canaline and gabaculine: structural basis for substrate recognition. Structure. 1997 Aug 15;5(8):1067-75. PMID:9309222
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