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1hj6

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{{STRUCTURE_1hj6| PDB=1hj6 | SCENE= }}
{{STRUCTURE_1hj6| PDB=1hj6 | SCENE= }}
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'''ISOCITRATE DEHYDROGENASE S113E MUTANT COMPLEXED WITH ISOPROPYLMALATE, NADP+ AND MAGNESIUM (FLASH-COOLED)'''
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===ISOCITRATE DEHYDROGENASE S113E MUTANT COMPLEXED WITH ISOPROPYLMALATE, NADP+ AND MAGNESIUM (FLASH-COOLED)===
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==Overview==
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Isocitrate dehydrogenase (IDH) catalyzes the oxidative decarboxylation of isocitrate and has negligible activity toward other (R)-malate-type substrates. The S113E mutant of IDH significantly improves its ability to utilize isopropylmalate as a substrate and switches the substrate specificity (k(cat)/K(M)) from isocitrate to isopropylmalate. To understand the structural basis for this switch in substrate specificity, we have determined the crystal structure of IDH S113E in a complex with isopropylmalate, NADP, and Mg(2+) to 2.0 A resolution. On the basis of a comparison with previously determined structures, we identify distinct changes caused by the amino acid substitution and by the binding of substrates. The S113E complex exhibits alterations in global and active site conformations compared with other IDH structures that include loop and helix conformational changes near the active site. In addition, the angle of the hinge that relates the two domains was altered in this structure, which suggests that the S113E substitution and the binding of substrates act together to promote catalysis of isopropylmalate. Ligand binding results in reorientation of the active site helix that contains residues 113 through 116. E113 exhibits new interactions, including van der Waals contacts with the isopropyl group of isopropylmalate and a hydrogen bond with N115, which in turn forms a hydrogen bond with NADP. In addition, the loop and helix regions that bind NADP are altered, as is the loop that connects the NADP binding region to the active site helix, changing the relationship between substrates and enzyme. In combination, these interactions appear to provide the basis for the switch in substrate specificity.
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{{ABSTRACT_PUBMED_11284679}}
==About this Structure==
==About this Structure==
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[[Category: Oxidoreductase]]
[[Category: Oxidoreductase]]
[[Category: Phosphorylation]]
[[Category: Phosphorylation]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Fri May 2 18:53:53 2008''
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Tue Jul 1 08:15:19 2008''

Revision as of 05:15, 1 July 2008

Image:1hj6.png

Template:STRUCTURE 1hj6

ISOCITRATE DEHYDROGENASE S113E MUTANT COMPLEXED WITH ISOPROPYLMALATE, NADP+ AND MAGNESIUM (FLASH-COOLED)

Template:ABSTRACT PUBMED 11284679

About this Structure

1HJ6 is a Single protein structure of sequence from Escherichia coli. Full crystallographic information is available from OCA.

Reference

Structural basis for a change in substrate specificity: crystal structure of S113E isocitrate dehydrogenase in a complex with isopropylmalate, Mg2+, and NADP., Doyle SA, Beernink PT, Koshland DE Jr, Biochemistry. 2001 Apr 10;40(14):4234-41. PMID:11284679

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