1kta
From Proteopedia
(New page: 200px<br /> <applet load="1kta" size="450" color="white" frame="true" align="right" spinBox="true" caption="1kta, resolution 1.90Å" /> '''HUMAN BRANCHED CHAI...) |
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caption="1kta, resolution 1.90Å" /> | caption="1kta, resolution 1.90Å" /> | ||
'''HUMAN BRANCHED CHAIN AMINO ACID AMINOTRANSFERASE : THREE DIMENSIONAL STRUCTURE OF THE ENZYME IN ITS PYRIDOXAMINE PHOSPHATE FORM.'''<br /> | '''HUMAN BRANCHED CHAIN AMINO ACID AMINOTRANSFERASE : THREE DIMENSIONAL STRUCTURE OF THE ENZYME IN ITS PYRIDOXAMINE PHOSPHATE FORM.'''<br /> | ||
==Overview== | ==Overview== | ||
| - | The three-dimensional structures of the isoleucine ketimine and the | + | The three-dimensional structures of the isoleucine ketimine and the pyridoxamine phosphate forms of human mitochondrial branched chain aminotransferase (hBCATm) have been determined crystallographically at 1.9 A resolution. The hBCATm-catalyzed transamination can be described in molecular terms together with the earlier solved pyridoxal phosphate forms of the enzyme. The active site lysine, Lys202, undergoes large conformational changes, and the pyridine ring of the cofactor tilts by about 18 degrees during catalysis. A major determinant of the enzyme's substrate and stereospecificity for L-branched chain amino acids is a group of hydrophobic residues that form three hydrophobic surfaces and lock the side chain in place. Short-chain aliphatic amino acid side chains are unable to interact through van der Waals contacts with any of the surfaces whereas bulky aromatic side chains would result in significant steric hindrance. As shown by modeling, and in agreement with previous biochemical data, glutamate but not aspartate can form hydrogen bond interactions. The carboxylate group of the bound isoleucine is on the same side as the phosphate group of the cofactor. These active site interactions are largely retained in a model of the human cytosolic branched chain aminotransferase (hBCATc), suggesting that residues in the second tier of interactions are likely to determine the specificity of hBCATc for the drug gabapentin. Finally, the structures reveal a unique role for cysteine residues in the mammalian BCAT. Cys315 and Cys318, which immediately follow a beta-turn (residues 311-314) and are located just outside the active site, form an unusual thiol-thiolate hydrogen bond. This beta-turn positions Thr313 for its interaction with the pyridoxal phosphate oxygens and substrate alpha-carboxylate group. |
==Disease== | ==Disease== | ||
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==About this Structure== | ==About this Structure== | ||
| - | 1KTA is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with KIV, PMP, ACY and GOL as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Branched-chain-amino-acid_transaminase Branched-chain-amino-acid transaminase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.6.1.42 2.6.1.42] Full crystallographic information is available from [http:// | + | 1KTA is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with <scene name='pdbligand=KIV:'>KIV</scene>, <scene name='pdbligand=PMP:'>PMP</scene>, <scene name='pdbligand=ACY:'>ACY</scene> and <scene name='pdbligand=GOL:'>GOL</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Branched-chain-amino-acid_transaminase Branched-chain-amino-acid transaminase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.6.1.42 2.6.1.42] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1KTA OCA]. |
==Reference== | ==Reference== | ||
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[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: Single protein]] | [[Category: Single protein]] | ||
| - | [[Category: Conway, M | + | [[Category: Conway, M E.]] |
| - | [[Category: Farber, G | + | [[Category: Farber, G K.]] |
| - | [[Category: Hutson, S | + | [[Category: Hutson, S M.]] |
| - | [[Category: Yennawar, H | + | [[Category: Yennawar, H P.]] |
| - | [[Category: Yennawar, N | + | [[Category: Yennawar, N H.]] |
[[Category: ACY]] | [[Category: ACY]] | ||
[[Category: GOL]] | [[Category: GOL]] | ||
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[[Category: fold type iv]] | [[Category: fold type iv]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 13:37:42 2008'' |
Revision as of 11:37, 21 February 2008
|
HUMAN BRANCHED CHAIN AMINO ACID AMINOTRANSFERASE : THREE DIMENSIONAL STRUCTURE OF THE ENZYME IN ITS PYRIDOXAMINE PHOSPHATE FORM.
Contents |
Overview
The three-dimensional structures of the isoleucine ketimine and the pyridoxamine phosphate forms of human mitochondrial branched chain aminotransferase (hBCATm) have been determined crystallographically at 1.9 A resolution. The hBCATm-catalyzed transamination can be described in molecular terms together with the earlier solved pyridoxal phosphate forms of the enzyme. The active site lysine, Lys202, undergoes large conformational changes, and the pyridine ring of the cofactor tilts by about 18 degrees during catalysis. A major determinant of the enzyme's substrate and stereospecificity for L-branched chain amino acids is a group of hydrophobic residues that form three hydrophobic surfaces and lock the side chain in place. Short-chain aliphatic amino acid side chains are unable to interact through van der Waals contacts with any of the surfaces whereas bulky aromatic side chains would result in significant steric hindrance. As shown by modeling, and in agreement with previous biochemical data, glutamate but not aspartate can form hydrogen bond interactions. The carboxylate group of the bound isoleucine is on the same side as the phosphate group of the cofactor. These active site interactions are largely retained in a model of the human cytosolic branched chain aminotransferase (hBCATc), suggesting that residues in the second tier of interactions are likely to determine the specificity of hBCATc for the drug gabapentin. Finally, the structures reveal a unique role for cysteine residues in the mammalian BCAT. Cys315 and Cys318, which immediately follow a beta-turn (residues 311-314) and are located just outside the active site, form an unusual thiol-thiolate hydrogen bond. This beta-turn positions Thr313 for its interaction with the pyridoxal phosphate oxygens and substrate alpha-carboxylate group.
Disease
Known diseases associated with this structure: Hypervalinemia or hyperleucine-isoleucinemia (1) OMIM:[113530]
About this Structure
1KTA is a Single protein structure of sequence from Homo sapiens with , , and as ligands. Active as Branched-chain-amino-acid transaminase, with EC number 2.6.1.42 Full crystallographic information is available from OCA.
Reference
Crystal structures of human mitochondrial branched chain aminotransferase reaction intermediates: ketimine and pyridoxamine phosphate forms., Yennawar NH, Conway ME, Yennawar HP, Farber GK, Hutson SM, Biochemistry. 2002 Oct 1;41(39):11592-601. PMID:12269802
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