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Titolo:
STRUCTURE OF 3-ISOPROPYLMALATE DEHYDROGENASE IN COMPLEX WITH NAD(- LIGAND-INDUCED LOOP CLOSING AND MECHANISM FOR COFACTOR SPECIFICITY() )
Autore:
HURLEY JH; DEAN AM;
Indirizzi:
NIDDKD,MOLEC BIOL LAB BETHESDA MD 20892 CHICAGO MED SCH,DEPT BIOL CHEM CHICAGO IL 60064
Titolo Testata:
Structure
fascicolo: 11, volume: 2, anno: 1994,
pagine: 1007 - 1016
SICI:
0969-2126(1994)2:11<1007:SO3DIC>2.0.ZU;2-8
Fonte:
ISI
Lingua:
ENG
Soggetto:
DEPENDENT ISOCITRATE DEHYDROGENASE; THERMUS-THERMOPHILUS; RESOLUTION; PROGRAM; ENZYME; PHOSPHORYLATION; DECARBOXYLATION; REFINEMENT; PROTEINS; GENE;
Keywords:
CONFORMATIONAL CHANGE; DINUCLEOTIDE-BINDING FOLD; ISOCITRATE DEHYDROGENASE; ISOPROPYLMALATE DEHYDROGENASE;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Science Citation Index Expanded
Science Citation Index Expanded
Citazioni:
28
Recensione:
Indirizzi per estratti:
Citazione:
J.H. Hurley e A.M. Dean, "STRUCTURE OF 3-ISOPROPYLMALATE DEHYDROGENASE IN COMPLEX WITH NAD(- LIGAND-INDUCED LOOP CLOSING AND MECHANISM FOR COFACTOR SPECIFICITY() )", Structure, 2(11), 1994, pp. 1007-1016

Abstract

Background: The leucine biosynthetic enzyme 3-isopropylmalate dehydrogenase (IMDH) belongs to a unique class of bifunctional decarboxylating dehydrogenases. The two best-known members of this family, IMDH and isocitrate dehydrogenase (IDH), share a common structural framework and catalytic mechanism but have different substrate and cofactor specificities. IMDH is NAD(+)-dependent, while IDHs occur in both NAD(+)-dependent and NADP(+)-dependent forms. Results: We have co-crystallized Thermus themophilus IMDH with NAD(+) and have determined the structure at 2.5 Angstrom resolution. NAD(+) binds in an extended conformation. Comparisons with the structure in the absence of cofactor show that binding induces structural changes of up to 2.5 Angstrom in the five loops which form the dinucleotide-binding site. The adenine and diphosphate moieties of NAD(+) are bound via interactions which are also present in the NADP(+)-IDH complex. Amino acids which interact with the NADP(+) 2'-phosphate in IDH are substituted or absent in IMDH. The adenosine ribose forms two hydrogen bonds with Asp278, and the nicotinamide and nicotinamide ribose interact with Glu87 and Asp78, all unique to IMDH. Conclusions: NAD(+) binding induces a conformational transition inIMDH, resulting in a structure that is intermediate between the most 'open' and 'closed' decarboxylating dehydrogenase conformations. Physiological specificity of IMDH for NAD(+) versus NADP(+) can be explained by the unique interaction between Asp278 and the free 2'-hydroxyl ofthe NAD(+) adenosine, discrimination against the presence of the 2'-phosphate by the negative charge on Asp278, and the absence of potential favorable interactions with the 2'-phosphate of NADP(+).

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Documento generato il 24/09/20 alle ore 20:50:50