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| - | [[Image:1wsv.gif|left|200px]] | |
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| - | {{Structure
| + | ==Crystal Structure of Human T-protein of Glycine Cleavage System== |
| - | |PDB= 1wsv |SIZE=350|CAPTION= <scene name='initialview01'>1wsv</scene>, resolution 2.60Å
| + | <StructureSection load='1wsv' size='340' side='right'caption='[[1wsv]], [[Resolution|resolution]] 2.60Å' scene=''> |
| - | |SITE=
| + | == Structural highlights == |
| - | |LIGAND= <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=THH:N-[4-({[(6S)-2-AMINO-4-HYDROXY-5-METHYL-5,6,7,8-TETRAHYDROPTERIDIN-6-YL]METHYL}AMINO)BENZOYL]-L-GLUTAMIC+ACID'>THH</scene> | + | <table><tr><td colspan='2'>[[1wsv]] is a 2 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=1WSV OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1WSV FirstGlance]. <br> |
| - | |ACTIVITY= <span class='plainlinks'>[http://en.wikipedia.org/wiki/Aminomethyltransferase Aminomethyltransferase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.1.2.10 2.1.2.10] </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]] 2.6Å</td></tr> |
| - | |GENE= GCST ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=THH:N-[4-({[(6S)-2-AMINO-4-HYDROXY-5-METHYL-5,6,7,8-TETRAHYDROPTERIDIN-6-YL]METHYL}AMINO)BENZOYL]-L-GLUTAMIC+ACID'>THH</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=1wsv FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1wsv OCA], [https://pdbe.org/1wsv PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1wsv RCSB], [https://www.ebi.ac.uk/pdbsum/1wsv PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1wsv ProSAT]</span></td></tr> |
| - | |RELATEDENTRY=[[1wsr|1WSR]]
| + | </table> |
| - | |RESOURCES=<span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1wsv FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1wsv OCA], [http://www.ebi.ac.uk/pdbsum/1wsv PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=1wsv RCSB]</span>
| + | == Disease == |
| - | }}
| + | [https://www.uniprot.org/uniprot/GCST_HUMAN GCST_HUMAN] Defects in AMT are a cause of non-ketotic hyperglycinemia (NKH) [MIM:[https://omim.org/entry/605899 605899]; also known as glycine encephalopathy (GCE). NKH is an autosomal recessive disease characterized by accumulation of a large amount of glycine in body fluid and by severe neurological symptoms.<ref>PMID:8005589</ref> <ref>PMID:9600239</ref> <ref>PMID:9621520</ref> <ref>PMID:10873393</ref> <ref>PMID:11286506</ref> |
| | + | == Function == |
| | + | [https://www.uniprot.org/uniprot/GCST_HUMAN GCST_HUMAN] The glycine cleavage system catalyzes the degradation of glycine. |
| | + | == 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/ws/1wsv_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=1wsv ConSurf]. |
| | + | <div style="clear:both"></div> |
| | + | <div style="background-color:#fffaf0;"> |
| | + | == Publication Abstract from PubMed == |
| | + | T-protein, a component of the glycine cleavage system, catalyzes the formation of ammonia and 5,10-methylenetetrahydrofolate from the aminomethyl moiety of glycine attached to the lipoate cofactor of H-protein. Several mutations in the human T-protein gene cause non-ketotic hyperglycinemia. To gain insights into the effect of disease-causing mutations and the catalytic mechanism at the molecular level, crystal structures of human T-protein in free form and that bound to 5-methyltetrahydrofolate (5-CH3-H4folate) have been determined at 2.0 A and 2.6 A resolution, respectively. The overall structure consists of three domains arranged in a cloverleaf-like structure with the central cavity, where 5-CH3-H4folate is bound in a kinked shape with the pteridine group deeply buried into the hydrophobic pocket and the glutamyl group pointed to the C-terminal side surface. Most of the disease-related residues cluster around the cavity, forming extensive hydrogen bonding networks. These hydrogen bonding networks are employed in holding not only the folate-binding space but also the positions and the orientations of alpha-helix G and the following loop in the middle region, which seems to play a pivotal role in the T-protein catalysis. Structural and mutational analyses demonstrated that Arg292 interacts through water molecules with the folate polyglutamate tail, and that the invariant Asp101, located close to the N10 group of 5-CH3-H4folate, might play a key role in the initiation of the catalysis by increasing the nucleophilic character of the N10 atom of the folate substrate for the nucleophilic attack on the aminomethyl lipoate intermediate. A clever mechanism of recruiting the aminomethyl lipoate arm to the reaction site seems to function as a way of avoiding the release of toxic formaldehyde. |
| | | | |
| - | '''Crystal Structure of Human T-protein of Glycine Cleavage System'''
| + | Crystal structure of human T-protein of glycine cleavage system at 2.0 A resolution and its implication for understanding non-ketotic hyperglycinemia.,Okamura-Ikeda K, Hosaka H, Yoshimura M, Yamashita E, Toma S, Nakagawa A, Fujiwara K, Motokawa Y, Taniguchi H J Mol Biol. 2005 Sep 2;351(5):1146-59. PMID:16051266<ref>PMID:16051266</ref> |
| | | | |
| | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> |
| | + | </div> |
| | + | <div class="pdbe-citations 1wsv" style="background-color:#fffaf0;"></div> |
| | | | |
| - | ==Overview== | + | ==See Also== |
| - | T-protein, a component of the glycine cleavage system, catalyzes the formation of ammonia and 5,10-methylenetetrahydrofolate from the aminomethyl moiety of glycine attached to the lipoate cofactor of H-protein. Several mutations in the human T-protein gene cause non-ketotic hyperglycinemia. To gain insights into the effect of disease-causing mutations and the catalytic mechanism at the molecular level, crystal structures of human T-protein in free form and that bound to 5-methyltetrahydrofolate (5-CH3-H4folate) have been determined at 2.0 A and 2.6 A resolution, respectively. The overall structure consists of three domains arranged in a cloverleaf-like structure with the central cavity, where 5-CH3-H4folate is bound in a kinked shape with the pteridine group deeply buried into the hydrophobic pocket and the glutamyl group pointed to the C-terminal side surface. Most of the disease-related residues cluster around the cavity, forming extensive hydrogen bonding networks. These hydrogen bonding networks are employed in holding not only the folate-binding space but also the positions and the orientations of alpha-helix G and the following loop in the middle region, which seems to play a pivotal role in the T-protein catalysis. Structural and mutational analyses demonstrated that Arg292 interacts through water molecules with the folate polyglutamate tail, and that the invariant Asp101, located close to the N10 group of 5-CH3-H4folate, might play a key role in the initiation of the catalysis by increasing the nucleophilic character of the N10 atom of the folate substrate for the nucleophilic attack on the aminomethyl lipoate intermediate. A clever mechanism of recruiting the aminomethyl lipoate arm to the reaction site seems to function as a way of avoiding the release of toxic formaldehyde.
| + | *[[Aminomethyltransferase 3D structures|Aminomethyltransferase 3D structures]] |
| - | | + | == References == |
| - | ==About this Structure==
| + | <references/> |
| - | 1WSV 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=1WSV OCA].
| + | __TOC__ |
| - | | + | </StructureSection> |
| - | ==Reference== | + | |
| - | Crystal structure of human T-protein of glycine cleavage system at 2.0 A resolution and its implication for understanding non-ketotic hyperglycinemia., Okamura-Ikeda K, Hosaka H, Yoshimura M, Yamashita E, Toma S, Nakagawa A, Fujiwara K, Motokawa Y, Taniguchi H, J Mol Biol. 2005 Sep 2;351(5):1146-59. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/16051266 16051266]
| + | |
| - | [[Category: Aminomethyltransferase]]
| + | |
| | [[Category: Homo sapiens]] | | [[Category: Homo sapiens]] |
| - | [[Category: Single protein]] | + | [[Category: Large Structures]] |
| - | [[Category: Fujiwara, K.]] | + | [[Category: Fujiwara K]] |
| - | [[Category: Hosaka, H.]] | + | [[Category: Hosaka H]] |
| - | [[Category: Motokawa, Y.]] | + | [[Category: Motokawa Y]] |
| - | [[Category: Nakagawa, A.]] | + | [[Category: Nakagawa A]] |
| - | [[Category: Okamura-Ikeda, K.]] | + | [[Category: Okamura-Ikeda K]] |
| - | [[Category: Taniguchi, H.]] | + | [[Category: Taniguchi H]] |
| - | [[Category: Toma, S.]] | + | [[Category: Toma S]] |
| - | [[Category: Yamashita, E.]] | + | [[Category: Yamashita E]] |
| - | [[Category: Yoshimura, M.]] | + | [[Category: Yoshimura M]] |
| - | [[Category: aminomethyl transferase]]
| + | |
| - | [[Category: glycine-cleavage sytem]]
| + | |
| - | | + | |
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Mar 31 00:40:31 2008''
| + | |
| Structural highlights
Disease
GCST_HUMAN Defects in AMT are a cause of non-ketotic hyperglycinemia (NKH) [MIM:605899; also known as glycine encephalopathy (GCE). NKH is an autosomal recessive disease characterized by accumulation of a large amount of glycine in body fluid and by severe neurological symptoms.[1] [2] [3] [4] [5]
Function
GCST_HUMAN The glycine cleavage system catalyzes the degradation of glycine.
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
T-protein, a component of the glycine cleavage system, catalyzes the formation of ammonia and 5,10-methylenetetrahydrofolate from the aminomethyl moiety of glycine attached to the lipoate cofactor of H-protein. Several mutations in the human T-protein gene cause non-ketotic hyperglycinemia. To gain insights into the effect of disease-causing mutations and the catalytic mechanism at the molecular level, crystal structures of human T-protein in free form and that bound to 5-methyltetrahydrofolate (5-CH3-H4folate) have been determined at 2.0 A and 2.6 A resolution, respectively. The overall structure consists of three domains arranged in a cloverleaf-like structure with the central cavity, where 5-CH3-H4folate is bound in a kinked shape with the pteridine group deeply buried into the hydrophobic pocket and the glutamyl group pointed to the C-terminal side surface. Most of the disease-related residues cluster around the cavity, forming extensive hydrogen bonding networks. These hydrogen bonding networks are employed in holding not only the folate-binding space but also the positions and the orientations of alpha-helix G and the following loop in the middle region, which seems to play a pivotal role in the T-protein catalysis. Structural and mutational analyses demonstrated that Arg292 interacts through water molecules with the folate polyglutamate tail, and that the invariant Asp101, located close to the N10 group of 5-CH3-H4folate, might play a key role in the initiation of the catalysis by increasing the nucleophilic character of the N10 atom of the folate substrate for the nucleophilic attack on the aminomethyl lipoate intermediate. A clever mechanism of recruiting the aminomethyl lipoate arm to the reaction site seems to function as a way of avoiding the release of toxic formaldehyde.
Crystal structure of human T-protein of glycine cleavage system at 2.0 A resolution and its implication for understanding non-ketotic hyperglycinemia.,Okamura-Ikeda K, Hosaka H, Yoshimura M, Yamashita E, Toma S, Nakagawa A, Fujiwara K, Motokawa Y, Taniguchi H J Mol Biol. 2005 Sep 2;351(5):1146-59. PMID:16051266[6]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Nanao K, Okamura-Ikeda K, Motokawa Y, Danks DM, Baumgartner ER, Takada G, Hayasaka K. Identification of the mutations in the T-protein gene causing typical and atypical nonketotic hyperglycinemia. Hum Genet. 1994 Jun;93(6):655-8. PMID:8005589
- ↑ Kure S, Mandel H, Rolland MO, Sakata Y, Shinka T, Drugan A, Boneh A, Tada K, Matsubara Y, Narisawa K. A missense mutation (His42Arg) in the T-protein gene from a large Israeli-Arab kindred with nonketotic hyperglycinemia. Hum Genet. 1998 Apr;102(4):430-4. PMID:9600239
- ↑ Kure S, Shinka T, Sakata Y, Osamu N, Takayanagi M, Tada K, Matsubara Y, Narisawa K. A one-base deletion (183delC) and a missense mutation (D276H) in the T-protein gene from a Japanese family with nonketotic hyperglycinemia. J Hum Genet. 1998;43(2):135-7. PMID:9621520 doi:10.1007/s100380050055
- ↑ Toone JR, Applegarth DA, Coulter-Mackie MB, James ER. Biochemical and molecular investigations of patients with nonketotic hyperglycinemia. Mol Genet Metab. 2000 Jun;70(2):116-21. PMID:10873393 doi:10.1006/mgme.2000.3000
- ↑ Toone JR, Applegarth DA, Coulter-Mackie MB, James ER. Recurrent mutations in P- and T-proteins of the glycine cleavage complex and a novel T-protein mutation (N145I): a strategy for the molecular investigation of patients with nonketotic hyperglycinemia (NKH). Mol Genet Metab. 2001 Apr;72(4):322-5. PMID:11286506 doi:10.1006/mgme.2001.3158
- ↑ Okamura-Ikeda K, Hosaka H, Yoshimura M, Yamashita E, Toma S, Nakagawa A, Fujiwara K, Motokawa Y, Taniguchi H. Crystal structure of human T-protein of glycine cleavage system at 2.0 A resolution and its implication for understanding non-ketotic hyperglycinemia. J Mol Biol. 2005 Sep 2;351(5):1146-59. PMID:16051266 doi:http://dx.doi.org/10.1016/j.jmb.2005.06.056
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