4qq6

Crystal Structure of tudor domain of SMN1 in complex with a small organic molecule

spinqualitylabelsall models 4qq6, resolution 1.75Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4qq6 is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.75Å Ligands: 36X, UNX Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function SMN_HUMAN Publication Abstract from PubMed Survival of motor neuron (SMN) functions in diverse biological pathways via recognition of symmetric dimethylarginine (Rme2s) on proteins by its Tudor domain, and deficiency of SMN leads to spinal muscular atrophy. Here we report a potent and selective antagonist with a 4-iminopyridine scaffold targeting the Tudor domain of SMN. Our structural and mutagenesis studies indicate that both the aromatic ring and imino groups of compound 1 contribute to its selective binding to SMN. Various on-target engagement assays support that compound 1 specifically recognizes SMN in a cellular context and prevents the interaction of SMN with the R1810me2s of RNA polymerase II subunit POLR2A, resulting in transcription termination and R-loop accumulation mimicking SMN depletion. Thus, in addition to the antisense, RNAi and CRISPR/Cas9 techniques, potent SMN antagonists could be used as an efficient tool to understand the biological functions of SMN. A small molecule antagonist of SMN disrupts the interaction between SMN and RNAP II.,Liu Y, Iqbal A, Li W, Ni Z, Wang Y, Ramprasad J, Abraham KJ, Zhang M, Zhao DY, Qin S, Loppnau P, Jiang H, Guo X, Brown PJ, Zhen X, Xu G, Mekhail K, Ji X, Bedford MT, Greenblatt JF, Min J Nat Commun. 2022 Sep 16;13(1):5453. doi: 10.1038/s41467-022-33229-5. PMID:36114190 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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