7B0T

Crystal structure of MLLT1 YEATS domain T3 mutant in complex with benzimidazole-amide based compound 1

Summary for 7B0T

• Entry DOI: 10.2210/pdb7b0t/pdb
• Descriptor: Protein ENL, 3-iodanyl-4-methyl-~{N}-[2-(piperidin-1-ylmethyl)-3~{H}-benzimidazol-5-yl]benzamide, 1,2-ETHANEDIOL, ... (4 entities in total)
• Functional Keywords: t3 mutant, structural genomics, structural genomics consortium, sgc, transcription
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 18830.53

Authors

Ni, X.,Chaikuad, A.,Brennan, P.E.,Knapp, S.,Structural Genomics Consortium (SGC) (deposition date: 2020-11-21, release date: 2021-02-17, Last modification date: 2024-01-31)

Primary citation

Ni, X.,Londregan, A.T.,Owen, D.R.,Knapp, S.,Chaikuad, A.
Structure and Inhibitor Binding Characterization of Oncogenic MLLT1 Mutants.
Acs Chem.Biol., 16:571-578, 2021

PubMed Abstract: Dysfunction of YEATS-domain-containing MLLT1, an acetyl/acyl-lysine dependent epigenetic reader domain, has been implicated in the development of aggressive cancers. Mutations in the YEATS domain have been recently reported as a cause of MLLT1 aberrant reader function. However, the structural basis for the reported alterations in affinity for acetylated/acylated histone has remained elusive. Here, we report the crystal structures of both insertion and substitution mutants present in cancer, revealing significant conformational changes of the YEATS-domain loop 8. Structural comparison demonstrates that not only did such alteration alter the binding interface for acetylated/acylated histones, but the sequence alterations in the loop in T1 mutant may enable dimeric assembly consistent with inducing self-association behavior. Nevertheless, we show that also the MLLT1 mutants can be targeted by developed acetyllysine mimetic inhibitors with affinities similarly to wild-type. Our report provides a structural basis for the altered behaviors and a potential strategy for targeting oncogenic MLLT1 mutants.

PubMed: 33749253
DOI: 10.1021/acschembio.0c00960

Experimental method

X-RAY DIFFRACTION (2.05 Å)