5BWW: X-ray Crystal Structure At 1.82a Resolution Of Human Mitochondrial Branched Chain Aminotransferase (bcatm) Complexed With A Pyrrolidine Amide Compound And An Internal Aldimine Linked Plp Cofactor

Citation:
Abstract
The hybridisation of hits, identified by complementary fragment and high throughput screens, enabled the discovery of the first series of potent inhibitors of mitochondrial branched-chain aminotransferase (BCATm), based on a 2-benzylamino-pyrazolo[1,5-a]pyrimidinone-3-carbonitrile template. Structure-guided growth enabled rapid optimisation of activity with maintenance of ligand efficiency, whilst the focus on physical properties delivered compounds with excellent pharmacokinetic exposure that enabled an acute proof of concept experiment in mice. Oral administration of 2-((4-chloro-2,6-difluorobenzyl)amino)-7-oxo-5-propyl-4,7-dihydropyrazolo[1,5-a]pyrimidine-3-carbonitrile 61 significantly raised the circulating levels of the branched-chain amino acids leucine, isoleucine and valine in this acute study.
PDB ID: 5BWWDownload
MMDB ID: 130629
PDB Deposition Date: 2015/6/8
Updated in MMDB: 2015/07
Experimental Method:
x-ray diffraction
Resolution: 1.82  Å
Source Organism:
Similar Structures:
Biological Unit for 5BWW: dimeric; determined by software (PISA)
Molecular Components in 5BWW
Label Count Molecule
Proteins (2 molecules)
2
Branched-chain-amino-acid Aminotransferase, Mitochondrial(Gene symbol: BCAT2)
Molecule annotation
Chemicals (23 molecules)
1
2
2
2
3
14
4
2
5
2
6
1
* Click molecule labels to explore molecular sequence information.

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