6VA4

Solution Structure of the Tau pre-mRNA Exon 10 Splicing Regulatory Element Bound to MIP

  • Classification: RNA
  • Organism(s): Homo sapiens
  • Mutation(s): No 

  • Deposited: 2019-12-16 Released: 2020-05-20 
  • Deposition Author(s): Chen, J.L., Fountain, M.A., Disney, M.D.
  • Funding Organization(s): National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS), National Institutes of Health/National Institute of Neurological Disorders and Stroke (NIH/NINDS)

Experimental Data Snapshot

  • Method: SOLUTION NMR
  • Conformers Calculated: 60 
  • Conformers Submitted: 20 
  • Selection Criteria: structures with the least restraint violations 

wwPDB Validation   3D Report Full Report


This is version 1.3 of the entry. See complete history


Literature

Design, Optimization, and Study of Small Molecules That Target Tau Pre-mRNA and Affect Splicing.

Chen, J.L.Zhang, P.Abe, M.Aikawa, H.Zhang, L.Frank, A.J.Zembryski, T.Hubbs, C.Park, H.Withka, J.Steppan, C.Rogers, L.Cabral, S.Pettersson, M.Wager, T.T.Fountain, M.A.Rumbaugh, G.Childs-Disney, J.L.Disney, M.D.

(2020) J Am Chem Soc 142: 8706-8727

  • DOI: https://doi.org/10.1021/jacs.0c00768
  • Primary Citation of Related Structures:  
    6VA1, 6VA2, 6VA3, 6VA4

  • PubMed Abstract: 

    Approximately 95% of human genes are alternatively spliced, and aberrant splicing events can cause disease. One pre-mRNA that is alternatively spliced and linked to neurodegenerative diseases is tau (microtubule-associated protein tau), which can cause frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) and can contribute to Alzheimer's disease. Here, we describe the design of structure-specific lead small molecules that directly target tau pre-mRNA from sequence. This was followed by hit expansion and analogue synthesis to further improve upon these initial lead molecules. The emergent compounds were assessed for functional activity in a battery of assays, including binding assays and an assay that mimics molecular recognition of tau pre-mRNA by a U1 small nuclear ribonucleoprotein (snRNP) splicing factor. Compounds that emerged from these studies had enhanced potency and selectivity for the target RNA relative to the initial hits, while also having significantly improved drug-like properties. The compounds are shown to directly target tau pre-mRNA in cells, via chemical cross-linking and isolation by pull-down target profiling, and to rescue disease-relevant splicing of tau pre-mRNA in a variety of cellular systems, including primary neurons. More broadly, this study shows that lead, structure-specific compounds can be designed from sequence and then further optimized for their physicochemical properties while at the same time enhancing their activity.


  • Organizational Affiliation

    Department of Chemistry and Neuroscience, The Scripps Research Institute, 130 Scripps Way, Jupiter, Florida 33458, United States.


Macromolecules

Find similar nucleic acids by:  Sequence   |   3D Structure  

Entity ID: 1
MoleculeChains LengthOrganismImage
RNA (5'-R(*CP*CP*GP*GP*CP*AP*GP*UP*GP*UP*G)-3')11Homo sapiens
Sequence Annotations
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  • Reference Sequence

Find similar nucleic acids by:  Sequence   |   3D Structure  

Entity ID: 2
MoleculeChains LengthOrganismImage
RNA (5'-R(*CP*AP*CP*AP*CP*GP*UP*CP*GP*G)-3')10Homo sapiens
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
QSY (Subject of Investigation/LOI)
Query on QSY

Download Ideal Coordinates CCD File 
C [auth B]N-[3-(8-methoxy-4-oxo-4,5-dihydro-3H-pyrimido[5,4-b]indol-3-yl)propyl]-N-methylcyclohexanaminium
C21 H29 N4 O2
ZZYFLPWOLNEUGF-UHFFFAOYSA-O
Experimental Data & Validation

Experimental Data

  • Method: SOLUTION NMR
  • Conformers Calculated: 60 
  • Conformers Submitted: 20 
  • Selection Criteria: structures with the least restraint violations 

Structure Validation

View Full Validation Report



Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)United StatesR01-GM097455-07
National Institutes of Health/National Institute of Neurological Disorders and Stroke (NIH/NINDS)United StatesDP1-NS096898
National Institutes of Health/National Institute of Neurological Disorders and Stroke (NIH/NINDS)United StatesP01-NS099114

Revision History  (Full details and data files)

  • Version 1.0: 2020-05-20
    Type: Initial release
  • Version 1.1: 2020-05-27
    Changes: Database references
  • Version 1.2: 2022-03-16
    Changes: Author supporting evidence, Database references
  • Version 1.3: 2024-05-15
    Changes: Data collection, Database references