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.

Summary for 5CR5

• Entry DOI: 10.2210/pdb5cr5/pdb
• Descriptor: 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)
• Functional Keywords: fold type iv, transferase
• Biological source: Homo sapiens (Human)
• Cellular location: Isoform A: Mitochondrion. Isoform B: Cytoplasm: O15382
• Total number of polymer chains: 2
• Total formula weight: 85623.51

Authors

Somers, D.O. (deposition date: 2015-07-22, release date: 2015-08-12, Last modification date: 2025-04-09)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (1.61 Å)