5CR5

X-RAY CRYSTAL STRUCTURE AT 1.61A RESOLUTION OF HUMAN MITOCHONDRIAL BRANCHED CHAIN AMINOTRANSFERASE (BCATM) COMPLEXED WITH A BIPHENYL PYRROLIDINE ETHER COMPOUND AND AN INTERNAL ALDIMINE LINKED PLP COFACTOR.

5CR5 の概要

• エントリーDOI: 10.2210/pdb5cr5/pdb
• 分子名称: Branched-chain-amino-acid aminotransferase, mitochondrial, PYRIDOXAL-5'-PHOSPHATE, 3-({(3R)-1-[(5-bromothiophen-2-yl)carbonyl]pyrrolidin-3-yl}oxy)-N-methyl-2'-[(methylsulfonyl)amino]biphenyl-4-carboxamide, ... (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)
• 細胞内の位置: Isoform A: Mitochondrion. Isoform B: Cytoplasm: O15382
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 85623.51

構造登録者

Somers, D.O. (登録日: 2015-07-22, 公開日: 2015-08-12, 最終更新日: 2015-09-02)

主引用文献

Deng, H.,Zhou, J.,Sundersingh, F.S.,Summerfield, J.,Somers, D.,Messer, J.A.,Satz, A.L.,Ancellin, N.,Arico-Muendel, C.C.,Sargent Bedard, K.L.,Beljean, A.,Belyanskaya, S.L.,Bingham, R.,Smith, S.E.,Boursier, E.,Carter, P.,Centrella, P.A.,Clark, M.A.,Chung, C.W.,Davie, C.P.,Delorey, J.L.,Ding, Y.,Franklin, G.J.,Grady, L.C.,Herry, K.,Hobbs, C.,Kollmann, C.S.,Morgan, B.A.,Pothier Kaushansky, L.J.,Zhou, Q.
Discovery, SAR, and X-ray Binding Mode Study of BCATm Inhibitors from a Novel DNA-Encoded Library.
Acs Med.Chem.Lett., 6:919-924, 2015

PubMed Abstract: As a potential target for obesity, human BCATm was screened against more than 14 billion DNA encoded compounds of distinct scaffolds followed by off-DNA synthesis and activity confirmation. As a consequence, several series of BCATm inhibitors were discovered. One representative compound (R)-3-((1-(5-bromothiophene-2-carbonyl)pyrrolidin-3-yl)oxy)-N-methyl-2'-(methylsulfonamido)-[1,1'-biphenyl]-4-carboxamide (15e) from a novel compound library synthesized via on-DNA Suzuki-Miyaura cross-coupling showed BCATm inhibitory activity with IC50 = 2.0 μM. A protein crystal structure of 15e revealed that it binds to BCATm within the catalytic site adjacent to the PLP cofactor. The identification of this novel inhibitor series plus the establishment of a BCATm protein structure provided a good starting point for future structure-based discovery of BCATm inhibitors.

PubMed: 26288694
DOI: 10.1021/acsmedchemlett.5b00179

実験手法

X-RAY DIFFRACTION (1.61 Å)