Crystal structure of human gamma-butyrobetaine hydroxylase

► Crystal structure of gamma-butyrobetaine hydroxylase solved at 2 Å resoluttion. ► Novel dimerization interface among 2-ketoglutarate oxygenases. ► Unique N-terminal Zn-containing domain. Gamma-butyrobetaine hydroxylase (GBBH) is a 2-ketoglutarate-dependent dioxygenase that catalyzes the biosynthes...

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Vydané v:Biochemical and biophysical research communications Ročník 398; číslo 4; s. 634 - 639
Hlavní autori: Tars, Kaspars, Rumnieks, Janis, Zeltins, Andris, Kazaks, Andris, Kotelovica, Svetlana, Leonciks, Ainars, Sharipo, Jelena, Viksna, Arturs, Kuka, Janis, Liepinsh, Edgars, Dambrova, Maija
Médium: Journal Article
Jazyk:English
Vydavateľské údaje: United States Elsevier Inc 06.08.2010
Predmet:
2-Ketoglutarate
Carnitine
Catalytic Domain
Crystal structure
Crystallography
Dioxygenase
Drug Design
Enzyme Inhibitors - chemistry
Enzyme Inhibitors - pharmacology
gamma-Butyrobetaine Dioxygenase - antagonists & inhibitors
gamma-Butyrobetaine Dioxygenase - chemistry
gamma-Butyrobetaine Dioxygenase - genetics
Gamma-buyrobetaine hydroxylase
Humans
Methylhydrazines - pharmacology
Mildronate
Protein Multimerization
Recombinant Proteins - chemistry
Recombinant Proteins - genetics
Zinc - chemistry
GBBH
Dioxygenase
2-Ketoglutarate
GBB
Gamma-buyrobetaine hydroxylase
Mildronate
DBSH
2KG
Carnitine
ISSN:0006-291X, 1090-2104, 1090-2104
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Shrnutí:► Crystal structure of gamma-butyrobetaine hydroxylase solved at 2 Å resoluttion. ► Novel dimerization interface among 2-ketoglutarate oxygenases. ► Unique N-terminal Zn-containing domain. Gamma-butyrobetaine hydroxylase (GBBH) is a 2-ketoglutarate-dependent dioxygenase that catalyzes the biosynthesis of l-carnitine by hydroxylation of gamma-butyrobetaine (GBB). l-carnitine is required for the transport of long-chain fatty acids into mitochondria for generating metabolic energy. The only known synthetic inhibitor of GBBH is mildronate (3-(2,2,2-trimethylhydrazinium) propionate dihydrate), which is a non-hydroxylatable analog of GBB. To aid in the discovery of novel GBBH inhibitors by rational drug design, we have solved the three-dimensional structure of recombinant human GBBH at 2.0 Å resolution. The GBBH monomer consists of a catalytic double-stranded β-helix (DBSH) domain, which is found in all 2KG oxygenases, and a smaller N-terminal domain. Extensive interactions between two monomers confirm earlier observations that GBBH is dimeric in its biological state. Although many 2KG oxygenases are multimeric, the dimerization interface of GBBH is very different from that of related enzymes. The N-terminal domain of GBBH has a similar fold to the DUF971 superfamily, which consists of several short bacterial proteins with unknown function. The N-terminal domain has a bound Zn ion, which is coordinated by three cysteines and one histidine. Although several other 2KG oxygenases with known structures have more than one domain, none of them resemble the N-terminal domain of GBBH. The N-terminal domain may facilitate dimer formation, but its precise biological role remains to be discovered. The active site of the catalytic domain of GBBH is similar to that of other 2KG oxygenases, and Fe(II)-binding residues form a conserved His–X–Asp–X n –His triad, which is found in all related enzymes.
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ISSN:0006-291X
1090-2104
1090-2104
DOI:10.1016/j.bbrc.2010.06.121