4C5W: Three Dimensional Structure of Human Gamma-butyrobetaine Hydroxylase in Complex With 4-(ethyldimethylammonio)butanoate

Citation:
Abstract
gamma-Butyrobetaine hydroxylase (BBOX) catalyzes the conversion of gamma butyrobetaine (GBB) to l-carnitine, which is involved in the generation of metabolic energy from long-chain fatty acids. BBOX inhibitor 3-(1,1,1-trimethylhydrazin-1-ium-2-yl)propanoate (mildronate), which is an approved, clinically used cardioprotective drug, is a relatively poor BBOX inhibitor and requires high daily doses. In this paper we describe the design, synthesis, and properties of 51 compounds, which include both GBB and mildronate analogues. We have discovered novel BBOX inhibitors with improved IC50 values; the best examples are in the nanomolar range and about 2 orders of magnitude better when compared to mildronate. For six inhibitors, crystal structures in complex with BBOX have been solved to explain their activities and pave the way for further inhibitor design.
PDB ID: 4C5WDownload
MMDB ID: 118188
PDB Deposition Date: 2013/9/16
Updated in MMDB: 2014/04
Experimental Method:
x-ray diffraction
Resolution: 1.7  Å
Source Organism:
Similar Structures:
Biological Unit for 4C5W: dimeric; determined by author and by software (PISA)
Molecular Components in 4C5W
Label Count Molecule
Proteins (2 molecules)
2
Gamma-butyrobetaine Dioxygenase(Gene symbol: BBOX1)
Molecule annotation
Chemicals (14 molecules)
1
2
2
2
3
8
4
2
* Click molecule labels to explore molecular sequence information.

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