9ckg
From Proteopedia
Crystal structure of SMYD2 active site mutant
Structural highlights
FunctionSMYD2_HUMAN Protein-lysine N-methyltransferase that methylates both histones and non-histone proteins. Specifically methylates histone H3 'Lys-4' (H3K4me) and dimethylates histone H3 'Lys-36' (H3K36me2). Has also methyltransferase activity toward non-histone proteins such as p53/TP53 and RB1. Monomethylates 'Lys-370' of p53/TP53, leading to decreased DNA-binding activity and subsequent transcriptional regulation activity of p53/TP53. Monomethylates 'Lys-860' of RB1/RB.[1] [2] [3] [4] Publication Abstract from PubMedAllosteric regulation allows proteins to dynamically respond to environmental cues by modulating activity at sites away from the catalytic center. Despite its importance, the SET-domain protein lysine methyltransferase superfamily has been understudied. Here, we present four crystal structures of SMYD2, a unique family member with a MYND domain. Our findings reveal a novel allosteric binding site with high conformational plasticity and promiscuity, capable of binding peptides, proteins, PEG, and small molecules. This site exhibits positive cooperativity with substrate binding, influencing catalytic activity. Mutations here significantly alter substrate affinity, changing the enzyme's kinetic profile. Specificity studies show interaction with PARP1 but not histones, suggesting targeted regulation. Interestingly, this site's function remains unaffected by active site changes, indicating unidirectional mechanisms. Our discovery provides novel insights into SMYD2's biochemical regulation and lays the foundation for broader research on allosteric control in lysine methyltransferases. Given SMYD2's role in various cancers, this work opens exciting avenues for designing specific allosteric inhibitors with reduced off-target effects. Structure of the SMYD2-PARP1 Complex Reveals Both Productive and Allosteric Modes of Peptide Binding.,Zhang Y, Alshammari E, Sobota J, Spellmon N, Perry E, Cao T, Mugunamalwaththa T, Smith S, Brunzelle J, Wu G, Stemmler T, Jin J, Li C, Yang Z bioRxiv [Preprint]. 2024 Dec 4:2024.12.03.626679. doi: 10.1101/2024.12.03.626679. PMID:39677743[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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Categories: Homo sapiens | Large Structures | Brunzelle J | Perry E | Sobota J | Spellmon N | Yang Z | Zhang Y
