1ohv: Difference between revisions

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==Overview==

Gamma-aminobutyric acid aminotransferase (GABA-AT) is a pyridoxal, 5'-phosphate-dependent enzyme responsible for the degradation of the, inhibitory neurotransmitter GABA. GABA-AT is a validated target for, antiepilepsy drugs because its selective inhibition raises GABA, concentrations in brain. The antiepilepsy drug, gamma-vinyl-GABA, (vigabatrin) has been investigated in the past by various biochemical, methods and resulted in several proposals for its mechanisms of, inactivation. In this study we solved and compared the crystal structures, of pig liver GABA-AT in its native form (to 2.3-A resolution) and in, complex with vigabatrin as well as with the close analogue, gamma-ethynyl-GABA (to 2.3 and 2.8 A, respectively). Both inactivators, form a covalent ternary adduct with the active site Lys-329 and the, pyridoxal 5'-phosphate (PLP) cofactor. The crystal structures provide, direct support for specific inactivation mechanisms proposed earlier on, the basis of radio-labeling experiments. The reactivity of GABA-AT, crystals with the two GABA analogues was also investigated by polarized, absorption microspectrophotometry. The spectral data are discussed in, relation to the proposed mechanism. Intriguingly, all three structures, revealed a [2Fe-2S] cluster of yet unknown function at the center of the, dimeric molecule in the vicinity of the PLP cofactors.

Gamma-aminobutyric acid aminotransferase (GABA-AT) is a pyridoxal 5'-phosphate-dependent enzyme responsible for the degradation of the inhibitory neurotransmitter GABA. GABA-AT is a validated target for antiepilepsy drugs because its selective inhibition raises GABA concentrations in brain. The antiepilepsy drug, gamma-vinyl-GABA (vigabatrin) has been investigated in the past by various biochemical methods and resulted in several proposals for its mechanisms of inactivation. In this study we solved and compared the crystal structures of pig liver GABA-AT in its native form (to 2.3-A resolution) and in complex with vigabatrin as well as with the close analogue gamma-ethynyl-GABA (to 2.3 and 2.8 A, respectively). Both inactivators form a covalent ternary adduct with the active site Lys-329 and the pyridoxal 5'-phosphate (PLP) cofactor. The crystal structures provide direct support for specific inactivation mechanisms proposed earlier on the basis of radio-labeling experiments. The reactivity of GABA-AT crystals with the two GABA analogues was also investigated by polarized absorption microspectrophotometry. The spectral data are discussed in relation to the proposed mechanism. Intriguingly, all three structures revealed a [2Fe-2S] cluster of yet unknown function at the center of the dimeric molecule in the vicinity of the PLP cofactors.

==About this Structure==

1OHV is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Sus_scrofa Sus scrofa] with <scene name='pdbligand=ACT:'>ACT</scene>, <scene name='pdbligand=FE:'>FE</scene>, <scene name='pdbligand=PLP:'>PLP</scene> and <scene name='pdbligand=S:'>S</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. This structure ~~superseeds~~ the now removed PDB entry 1GTX. Active as [http://en.wikipedia.org/wiki/4-aminobutyrate_transaminase 4-aminobutyrate transaminase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.6.1.19 2.6.1.19] Known structural/functional Site: <scene name='pdbsite=AC1:S+Binding+Site+For+Chain+D'>AC1</scene>. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1OHV OCA].

1OHV is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Sus_scrofa Sus scrofa] with <scene name='pdbligand=ACT:'>ACT</scene>, <scene name='pdbligand=FE:'>FE</scene>, <scene name='pdbligand=PLP:'>PLP</scene> and <scene name='pdbligand=S:'>S</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. This structure supersedes the now removed PDB entry 1GTX. Active as [http://en.wikipedia.org/wiki/4-aminobutyrate_transaminase 4-aminobutyrate transaminase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.6.1.19 2.6.1.19] Known structural/functional Site: <scene name='pdbsite=AC1:S+Binding+Site+For+Chain+D'>AC1</scene>. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1OHV OCA].

==Reference==

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[[Category: transferase]]

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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 14:17:54 2008''

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@@ Line 4: / Line 4: @@
 ==Overview==
-Gamma-aminobutyric acid aminotransferase (GABA-AT) is a pyridoxal, 5'-phosphate-dependent enzyme responsible for the degradation of the, inhibitory neurotransmitter GABA. GABA-AT is a validated target for, antiepilepsy drugs because its selective inhibition raises GABA, concentrations in brain. The antiepilepsy drug, gamma-vinyl-GABA, (vigabatrin) has been investigated in the past by various biochemical, methods and resulted in several proposals for its mechanisms of, inactivation. In this study we solved and compared the crystal structures, of pig liver GABA-AT in its native form (to 2.3-A resolution) and in, complex with vigabatrin as well as with the close analogue, gamma-ethynyl-GABA (to 2.3 and 2.8 A, respectively). Both inactivators, form a covalent ternary adduct with the active site Lys-329 and the, pyridoxal 5'-phosphate (PLP) cofactor. The crystal structures provide, direct support for specific inactivation mechanisms proposed earlier on, the basis of radio-labeling experiments. The reactivity of GABA-AT, crystals with the two GABA analogues was also investigated by polarized, absorption microspectrophotometry. The spectral data are discussed in, relation to the proposed mechanism. Intriguingly, all three structures, revealed a [2Fe-2S] cluster of yet unknown function at the center of the, dimeric molecule in the vicinity of the PLP cofactors.
+Gamma-aminobutyric acid aminotransferase (GABA-AT) is a pyridoxal 5'-phosphate-dependent enzyme responsible for the degradation of the inhibitory neurotransmitter GABA. GABA-AT is a validated target for antiepilepsy drugs because its selective inhibition raises GABA concentrations in brain. The antiepilepsy drug, gamma-vinyl-GABA (vigabatrin) has been investigated in the past by various biochemical methods and resulted in several proposals for its mechanisms of inactivation. In this study we solved and compared the crystal structures of pig liver GABA-AT in its native form (to 2.3-A resolution) and in complex with vigabatrin as well as with the close analogue gamma-ethynyl-GABA (to 2.3 and 2.8 A, respectively). Both inactivators form a covalent ternary adduct with the active site Lys-329 and the pyridoxal 5'-phosphate (PLP) cofactor. The crystal structures provide direct support for specific inactivation mechanisms proposed earlier on the basis of radio-labeling experiments. The reactivity of GABA-AT crystals with the two GABA analogues was also investigated by polarized absorption microspectrophotometry. The spectral data are discussed in relation to the proposed mechanism. Intriguingly, all three structures revealed a [2Fe-2S] cluster of yet unknown function at the center of the dimeric molecule in the vicinity of the PLP cofactors.
 ==About this Structure==
-OHV is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Sus_scrofa Sus scrofa] with <scene name='pdbligand=ACT:'>ACT</scene>, <scene name='pdbligand=FE:'>FE</scene>, <scene name='pdbligand=PLP:'>PLP</scene> and <scene name='pdbligand=S:'>S</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. This structure superseeds the now removed PDB entry 1GTX. Active as [http://en.wikipedia.org/wiki/4-aminobutyrate_transaminase 4-aminobutyrate transaminase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.6.1.19 2.6.1.19] Known structural/functional Site: <scene name='pdbsite=AC1:S+Binding+Site+For+Chain+D'>AC1</scene>. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1OHV OCA].
+OHV is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Sus_scrofa Sus scrofa] with <scene name='pdbligand=ACT:'>ACT</scene>, <scene name='pdbligand=FE:'>FE</scene>, <scene name='pdbligand=PLP:'>PLP</scene> and <scene name='pdbligand=S:'>S</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. This structure supersedes the now removed PDB entry 1GTX. Active as [http://en.wikipedia.org/wiki/4-aminobutyrate_transaminase 4-aminobutyrate transaminase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.6.1.19 2.6.1.19] Known structural/functional Site: <scene name='pdbsite=AC1:S+Binding+Site+For+Chain+D'>AC1</scene>. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1OHV OCA].
 ==Reference==
@@ Line 26: / Line 26: @@
 [[Category: transferase]]
-''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun Feb  3 09:58:18 2008''
+''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 14:17:54 2008''