8DKB

Crystal Structure of human YEATS4 in complex with Pfizer small molecule compound 3b

Summary for 8DKB

• Entry DOI: 10.2210/pdb8dkb/pdb
• Descriptor: YEATS domain-containing protein 4, N-ethyl-1-{(3S,4S)-1-[(1-hydroxycyclohexyl)methyl]-3-methylpiperidin-4-yl}-2-methyl-1H-benzimidazole-5-carboxamide (3 entities in total)
• Functional Keywords: protein binding, histone binding, lysine-acetylated histone binding
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 8
• Total formula weight: 149147.62

Authors

Dias, J.M.,Byrnes, L.J.,Varghese, A.H. (deposition date: 2022-07-05, release date: 2023-01-11, Last modification date: 2023-10-25)

Primary citation

Londregan, A.T.,Aitmakhanova, K.,Bennett, J.,Byrnes, L.J.,Canterbury, D.P.,Cheng, X.,Christott, T.,Clemens, J.,Coffey, S.B.,Dias, J.M.,Dowling, M.S.,Farnie, G.,Fedorov, O.,Fennell, K.F.,Gamble, V.,Gileadi, C.,Giroud, C.,Harris, M.R.,Hollingshead, B.D.,Huber, K.,Korczynska, M.,Lapham, K.,Loria, P.M.,Narayanan, A.,Owen, D.R.,Raux, B.,Sahasrabudhe, P.V.,Ruggeri, R.B.,Saez, L.D.,Stock, I.A.,Thuma, B.A.,Tsai, A.,Varghese, A.E.
Discovery of High-Affinity Small-Molecule Binders of the Epigenetic Reader YEATS4.
J.Med.Chem., 66:460-472, 2023

PubMed Abstract: A series of small-molecule YEATS4 binders have been discovered as part of an ongoing research effort to generate high-quality probe molecules for emerging and/or challenging epigenetic targets. Analogues such as and demonstrate excellent potency and selectivity for YEATS4 binding versus YEATS1,2,3 and exhibit good physical properties and in vitro safety profiles. A new X-ray crystal structure confirms direct binding of this chemical series to YEATS4 at the lysine acetylation recognition site of the YEATS domain. Multiple analogues engage YEATS4 with nanomolar potency in a whole-cell nanoluciferase bioluminescent resonance energy transfer assay. Rodent pharmacokinetic studies demonstrate the competency of several analogues as in vivo-capable binders.

PubMed: 36562986
DOI: 10.1021/acs.jmedchem.2c01421

Experimental method

X-RAY DIFFRACTION (2.58 Å)