29tn
KAT8 MUTANT (KAT6A SURROGATE, MYST-CRYST) IN COMPLEX WITH KAT6A INHIBITOR COMPOUND 38
Structural highlights
FunctionKAT8_HUMAN Histone acetyltransferase which may be involved in transcriptional activation. May influence the function of ATM. As part of the MSL complex it is involved in acetylation of nucleosomal histone H4 producing specifically H4K16ac. As part of the NSL complex it may be involved in acetylation of nucleosomal histone H4 on several lysine residues. That activity is less specific than the one of the MSL complex.[1] [2] [3] Publication Abstract from PubMedThe histone lysine acetyltransferase KAT6A belongs to the MYST family of lysine acetyltransferases which consists of five isoforms. KAT6A (and its paralog KAT6B) have emerged as a promising epigenetic drug targets in cancer, supported by recent clinical data. As support for our high-throughput screening approach aimed at discovering new inhibitors of KAT6A, we developed a crystallization platform system termed KAT6A(mutCys) in which four surface cysteine residues of KAT6A were mutated to serine. This construct crystallizes readily when in complex with its cofactor AcCoA. The obtained co-crystals were successfully used in a back-soaking approach in which AcCoA was soaked out of the crystals and small-molecule inhibitors were soaked in. In parallel, we explored a previously published surrogate approach termed MYST(cryst) in which active-site residues of the related, but easier to crystallize, enzyme KAT8 were mutated to those found in KAT6A. By comparing co-crystal structures of the same ligand bound to KAT6A from our Cys-to-Ser approach and to mutated KAT8 (MYST(cryst)) we found that the KAT8 surrogate approach indeed successfully reproduced the binding mode observed in the KAT6A structure, while delivering structures with significantly higher resolution. The MYST(cryst) approach was therefore employed to determine the binding modes of two further small-molecule inhibitors, both from our KAT6A inhibitor optimization program and from a competitor lead series. These structures reveal alternative inhibitor conformations at the binding-site entry and the importance of filling a hydrophobic subpocket in the interior of the binding pocket. These insights will aid future efforts towards the development of KAT6A inhibitors as anticancer drugs. KAT6A-inhibitor co-crystal structures: tackling a challenging crystallization target via two alternative approaches.,Puetter V, Bouche L, Nowak-Reppel K, Ferrara SJ, Gradl SN, Korr D, Strathdee CA, Ter Laak A, Hillig RC Acta Crystallogr D Struct Biol. 2026 Sep 1;82(Pt 9):1111-1124. doi: , 10.1107/S2059798326008545. Epub 2026 Aug 27. PMID:42657771[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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