6Q8J

Nterminal domain of human SMU1 in complex with LSP641

Summary for 6Q8J

• Entry DOI: 10.2210/pdb6q8j/pdb
• Related: 6Q8F 6Q8I
• Descriptor: WD40 repeat-containing protein SMU1, 1-~{tert}-butyl-3-[6-(3,5-dimethoxyphenyl)-2-[[1-[1-(phenylmethyl)piperidin-4-yl]-1,2,3-triazol-4-yl]methylamino]pyrido[2,3-d]pyrimidin-7-yl]urea (3 entities in total)
• Functional Keywords: splicing factor, influenza virus, splicing
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 23416.98

Authors

Tengo, L.,Le Corre, L.,Fournier, G.,Ashraf, U.,Busca, P.,Rameix-Welti, M.-A.,Gravier-Pelletier, C.,Ruigrok, R.W.H.,Jacob, Y.,Vidalain, P.-O.,Pietrancosta, N.,Naffakh, N.,McCarthy, A.A.,Crepin, T. (deposition date: 2018-12-14, release date: 2019-05-22, Last modification date: 2024-01-24)

Primary citation

Ashraf, U.,Tengo, L.,Le Corre, L.,Fournier, G.,Busca, P.,McCarthy, A.A.,Rameix-Welti, M.A.,Gravier-Pelletier, C.,Ruigrok, R.W.H.,Jacob, Y.,Vidalain, P.O.,Pietrancosta, N.,Crepin, T.,Naffakh, N.
Destabilization of the human RED-SMU1 splicing complex as a basis for host-directed antiinfluenza strategy.
Proc.Natl.Acad.Sci.USA, 116:10968-10977, 2019

PubMed Abstract: New therapeutic strategies targeting influenza are actively sought due to limitations in current drugs available. Host-directed therapy is an emerging concept to target host functions involved in pathogen life cycles and/or pathogenesis, rather than pathogen components themselves. From this perspective, we focused on an essential host partner of influenza viruses, the RED-SMU1 splicing complex. Here, we identified two synthetic molecules targeting an α-helix/groove interface essential for RED-SMU1 complex assembly. We solved the structure of the SMU1 N-terminal domain in complex with RED or bound to one of the molecules identified to disrupt this complex. We show that these compounds inhibiting RED-SMU1 interaction also decrease endogenous RED-SMU1 levels and inhibit viral mRNA splicing and viral multiplication, while preserving cell viability. Overall, our data demonstrate the potential of RED-SMU1 destabilizing molecules as an antiviral therapy that could be active against a wide range of influenza viruses and be less prone to drug resistance.

PubMed: 31076555
DOI: 10.1073/pnas.1901214116

Experimental method

X-RAY DIFFRACTION (1.8 Å)