4QQ6

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

Summary for 4QQ6

• Entry DOI: 10.2210/pdb4qq6/pdb
• Descriptor: Survival motor neuron protein, UNKNOWN ATOM OR ION, 4-methyl-2,3,4,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8(1H)-imine, ... (4 entities in total)
• Functional Keywords: structural genomics, structural genomics consortium, sgc, rna binding protein
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm: Q16637
• Total number of polymer chains: 1
• Total formula weight: 7597.57

Authors

Liu, Y.,Tempel, W.,Iqbal, A.,Walker, J.R.,Bountra, C.,Arrowsmith, C.H.,Edwards, A.M.,Brown, P.J.,Min, J.,Structural Genomics Consortium (SGC) (deposition date: 2014-06-26, release date: 2014-08-06, Last modification date: 2023-09-20)

Primary citation

Liu, Y.,Iqbal, A.,Li, W.,Ni, Z.,Wang, Y.,Ramprasad, J.,Abraham, K.J.,Zhang, M.,Zhao, D.Y.,Qin, S.,Loppnau, P.,Jiang, H.,Guo, X.,Brown, P.J.,Zhen, X.,Xu, G.,Mekhail, K.,Ji, X.,Bedford, M.T.,Greenblatt, J.F.,Min, J.
A small molecule antagonist of SMN disrupts the interaction between SMN and RNAP II.
Nat Commun, 13:5453-5453, 2022

PubMed Abstract: 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.

PubMed: 36114190
DOI: 10.1038/s41467-022-33229-5

Experimental method

X-RAY DIFFRACTION (1.75 Å)