29uq
KAT6A SURFACE MUTANT IN COMPLEX WITH CO-FACTOR ACETYL-CO-A
Structural highlights
DiseaseKAT6A_HUMAN Note=Chromosomal aberrations involving KAT6A may be a cause of acute myeloid leukemias. Translocation t(8;16)(p11;p13) with CREBBP; translocation t(8;22)(p11;q13) with EP300. KAT6A-CREBBP may induce leukemia by inhibiting RUNX1-mediated transcription. Inversion inv(8)(p11;q13) generates the KAT6A-NCOA2 oncogene, which consists of the N-terminal part of KAT6A and the C-terminal part of NCOA2/TIF2. KAT6A-NCOA2 binds to CREBBP and disrupts its function in transcription activation. Note=A chromosomal aberration involving KAT6A is a cause of therapy-related myelodysplastic syndrome. Translocation t(2;8)(p23;p11.2) with ASXL2 generates a KAT6A-ASXL2 fusion protein. FunctionKAT6A_HUMAN Histone acetyltransferase that acetylates lysine residues in histone H3 and histone H4 (in vitro). Component of the MOZ/MORF complex which has a histone H3 acetyltransferase activity. May act as a transcriptional coactivator for RUNX1 and RUNX2.[1] [2] [3] [4] [5] 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[6] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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