5TPX

Bromodomain from Plasmodium Faciparum Gcn5, complexed with compound

Summary for 5TPX

• Entry DOI: 10.2210/pdb5tpx/pdb
• Related: 4QNS
• Descriptor: Histone acetyltransferase GCN5, CHLORIDE ION, SULFATE ION, ... (5 entities in total)
• Functional Keywords: bromodomain, transferase, structural genomics consortium (sgc)
• Biological source: Plasmodium falciparum (isolate 3D7)
• Total number of polymer chains: 1
• Total formula weight: 15449.90

Authors

Lin, Y.H.,Hou, C.F.D.,MOUSTAKIM, M.,DIXON, D.J.,Loppnau, P.,Tempel, W.,Bountra, C.,Edwards, A.M.,Arrowsmith, C.H.,Hui, R.,BRENNAN, P.E.,Walker, J.R.,Structural Genomics Consortium (SGC) (deposition date: 2016-10-21, release date: 2017-01-04, Last modification date: 2023-10-04)

Primary citation

Moustakim, M.,Clark, P.G.,Trulli, L.,Fuentes de Arriba, A.L.,Ehebauer, M.T.,Chaikuad, A.,Murphy, E.J.,Mendez-Johnson, J.,Daniels, D.,Hou, C.D.,Lin, Y.H.,Walker, J.R.,Hui, R.,Yang, H.,Dorrell, L.,Rogers, C.M.,Monteiro, O.P.,Fedorov, O.,Huber, K.V.,Knapp, S.,Heer, J.,Dixon, D.J.,Brennan, P.E.
Discovery of a PCAF Bromodomain Chemical Probe.
Angew. Chem. Int. Ed. Engl., 56:827-831, 2017

PubMed Abstract: The p300/CBP-associated factor (PCAF) and related GCN5 bromodomain-containing lysine acetyl transferases are members of subfamily I of the bromodomain phylogenetic tree. Iterative cycles of rational inhibitor design and biophysical characterization led to the discovery of the triazolopthalazine-based L-45 (dubbed L-Moses) as the first potent, selective, and cell-active PCAF bromodomain (Brd) inhibitor. Synthesis from readily available (1R,2S)-(-)-norephedrine furnished L-45 in enantiopure form. L-45 was shown to disrupt PCAF-Brd histone H3.3 interaction in cells using a nanoBRET assay, and a co-crystal structure of L-45 with the homologous Brd PfGCN5 from Plasmodium falciparum rationalizes the high selectivity for PCAF and GCN5 bromodomains. Compound L-45 shows no observable cytotoxicity in peripheral blood mononuclear cells (PBMC), good cell-permeability, and metabolic stability in human and mouse liver microsomes, supporting its potential for in vivo use.

PubMed: 27966810
DOI: 10.1002/anie.201610816

Experimental method

X-RAY DIFFRACTION (2.1 Å)