3N6W

Crystal structure of human gamma-butyrobetaine hydroxylase

Summary for 3N6W

• Entry DOI: 10.2210/pdb3n6w/pdb
• Descriptor: Gamma-butyrobetaine dioxygenase, ZINC ION, SULFATE ION, ... (4 entities in total)
• Functional Keywords: gamma-butyrobetaine hydroxylase, bbh, dioxygenase, carnitine, hydrolase, oxidoreductase
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm: O75936
• Total number of polymer chains: 1
• Total formula weight: 47304.81

Authors

Rumnieks, J.,Zeltins, A.,Leonchiks, A.,Kazaks, A.,Kotelovica, S.,Tars, K. (deposition date: 2010-05-26, release date: 2010-07-21, Last modification date: 2024-02-21)

Primary citation

Tars, K.,Rumnieks, J.,Zeltins, A.,Kazaks, A.,Kotelovica, S.,Leonciks, A.,Sharipo, J.,Viksna, A.,Kuka, J.,Liepinsh, E.,Dambrova, M.
Crystal structure of human gamma-butyrobetaine hydroxylase.
Biochem.Biophys.Res.Commun., 398:634-639, 2010

PubMed Abstract: 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 2.0A resolution. The GBBH monomer consists of a catalytic double-stranded beta-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.

PubMed: 20599753
DOI: 10.1016/j.bbrc.2010.06.121

Experimental method

X-RAY DIFFRACTION (2 Å)