4C8R

Human gamma-butyrobetaine dioxygenase (BBOX1) in complex with Ni(II) and N-(3-hydroxypicolinoyl)-S-(pyridin-2-ylmethyl)-L-cysteine (AR692B)

Summary for 4C8R

• Entry DOI: 10.2210/pdb4c8r/pdb
• Descriptor: GAMMA-BUTYROBETAINE DIOXYGENASE, NICKEL (II) ION, ZINC ION, ... (6 entities in total)
• Functional Keywords: oxidoreductase, non-heme, iron, 2-oxoglutarate, dioxygenase 1, dsbh, facial triad, gamma-butyrobetaine, hydroxylase
• Biological source: HOMO SAPIENS (HUMAN)
• Total number of polymer chains: 6
• Total formula weight: 272785.41

Authors

Chowdhury, R.,Rydzik, A.M.,Kochan, G.T.,McDonough, M.A.,Schofield, C.J. (deposition date: 2013-10-01, release date: 2014-05-14, Last modification date: 2023-12-20)

Primary citation

Rydzik, A.M.,Chowdhury, R.,Kochan, G.T.,Williams, S.T.,McDonough, M.A.,Kawamura, A.,Schofield, C.J.
Modulating carnitine levels by targeting its biosynthesis pathway - selective inhibition of gamma-butyrobetaine hydroxylase.
Chem Sci, 5:1765-1771, 2014

PubMed Abstract: Carnitine is essential for fatty acid metabolism, but is associated with both health benefits and risks, especially heart diseases. We report the identification of potent, selective and cell active inhibitors of γ-butyrobetaine hydroxylase (BBOX), which catalyses the final step of carnitine biosynthesis in animals. A crystal structure of BBOX in complex with a lead inhibitor reveals that it binds in two modes, one of which adopts an unusual 'U-shape' conformation stabilised by inter- and intra-molecular π-stacking interactions. Conformational changes observed on binding of the inhibitor to BBOX likely reflect those occurring in catalysis; they also rationalise the inhibition of BBOX by high levels of its substrate γ-butyrobetaine (GBB), as observed both with isolated BBOX protein and in cellular studies.

PubMed: 26682037
DOI: 10.1039/C4SC00020J

Experimental method

X-RAY DIFFRACTION (2.82 Å)