5BWT

X-RAY CRYSTAL STRUCTURE AT 2.20A RESOLUTION OF HUMAN MITOCHONDRIAL BRANCHED CHAIN AMINOTRANSFERASE (BCATM) COMPLEXED WITH A PYRAZOLOPYRIMIDINONE FRAGMENT AND AN INTERNAL ALDIMINE LINKED PLP.

5BWT の概要

• エントリーDOI: 10.2210/pdb5bwt/pdb
• 分子名称: Branched-chain-amino-acid aminotransferase, mitochondrial, PYRIDOXAL-5'-PHOSPHATE, 5-ethyl-2-methyl-7-oxo-4,7-dihydropyrazolo[1,5-a]pyrimidine-3-carbonitrile, ... (7 entities in total)
• 機能のキーワード: fold type iv, transferase
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 84920.35

構造登録者

Somers, D.O. (登録日: 2015-06-08, 公開日: 2015-07-01, 最終更新日: 2025-04-09)

主引用文献

Bertrand, S.M.,Ancellin, N.,Beaufils, B.,Bingham, R.P.,Borthwick, J.A.,Boullay, A.B.,Boursier, E.,Carter, P.S.,Chung, C.W.,Churcher, I.,Dodic, N.,Fouchet, M.H.,Fournier, C.,Francis, P.L.,Gummer, L.A.,Herry, K.,Hobbs, A.,Hobbs, C.I.,Homes, P.,Jamieson, C.,Nicodeme, E.,Pickett, S.D.,Reid, I.H.,Simpson, G.L.,Sloan, L.A.,Smith, S.E.,Somers, D.O.,Spitzfaden, C.,Suckling, C.J.,Valko, K.,Washio, Y.,Young, R.J.
The Discovery of in Vivo Active Mitochondrial Branched-Chain Aminotransferase (BCATm) Inhibitors by Hybridizing Fragment and HTS Hits.
J.Med.Chem., 58:7140-7163, 2015

PubMed Abstract: The hybridization 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 optimization of potency with maintenance of ligand efficiency, while the focus on physicochemical properties delivered compounds with excellent pharmacokinetic exposure that enabled a 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.

PubMed: 26090771
DOI: 10.1021/acs.jmedchem.5b00313

実験手法

X-RAY DIFFRACTION (2.2 Å)