ArticleChannels (Austin, Tex.)2018
Chemical shift perturbation mapping of the Ubc9-CRMP2 interface identifies a pocket in CRMP2 amenable for allosteric modulation of Nav1.7 channels.
Article in Channels (Austin, Tex.), 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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Who cites it
13 citing papers in PubMed, 20 citations in OpenAlex.
- Article
- Peptide and Peptidomimetic Inhibitors Targeting the Interaction of Collapsin Response Mediator Protein 2 with the N-Type Calcium Channel for Pain Relief.ACS pharmacology & translational science · 2024Review
- SUMOylation of the cardiac sodium channel NaHeart rhythm · 2023Article
- Small molecule targeting NaV1.7 via inhibition of the CRMP2-Ubc9 interaction reduces pain in chronic constriction injury (CCI) rats.Channels (Austin, Tex.) · 2022Article
- Changes in peripheral HCN2 channels during persistent inflammation.Channels (Austin, Tex.) · 2021Article
- Selective targeting of NaV1.7 via inhibition of the CRMP2-Ubc9 interaction reduces pain in rodents.Science translational medicine · 2021Article
- Applications of Solution NMR in Drug Discovery.Molecules (Basel, Switzerland) · 2021Review
- Role of the Ubiquitin System in Chronic Pain.Frontiers in molecular neuroscience · 2021Review
- The 2019 FASEB Science Research Conference on Ion Channel Regulation: Molecules to Disease, July 7-12, 2019, Lisbon, Portugal.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2020Article
- Dysregulation of CRMP2 Post-Translational Modifications Drive Its Pathological Functions.Molecular neurobiology · 2019Review
- SUMOylation regulates USP5-Cav3.2 calcium channel interactions.Molecular brain · 2019Article
- Mining the NaBiochemical pharmacology · 2019Review
- Small molecule targeting NaV1.7 via inhibition of the CRMP2-Ubc9 interaction reduces and prevents pain chronification in a mouse model of oxaliplatin-induced neuropathic pain.Neurobiology of pain (Cambridge, Mass.)Article
Corrections and comments
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Authors and funding
6 authors at 1 institution in 1 country.
Funding
Abstract
Drug discovery campaigns directly targeting the voltage-gated sodium channel NaV1.7, a highly prized target in chronic pain, have not yet been clinically successful. In a differentiated approach, we demonstrated allosteric control of trafficking and activity of NaV1.7 by prevention of SUMOylation of collapsin response mediator protein 2 (CRMP2). Spinal administration of a SUMOylation incompetent CRMP2 (CRMP2 K374A) significantly attenuated pain behavior in the spared nerve injury (SNI) model of neuropathic pain, underscoring the importance of SUMOylation of CRMP2 as a pathologic event in chronic pain. Using a rational design strategy, we identified a heptamer peptide harboring CRMP2's SUMO motif that disrupted the CRMP2-Ubc9 interaction, inhibited CRMP2 SUMOylation, inhibited NaV1.7 membrane trafficking, and specifically inhibited NaV1.7 sodium influx in sensory neurons. Importantly, this peptide reversed nerve injury-induced thermal and mechanical hypersensitivity in the SNI model, supporting the practicality of discovering pain drugs by indirectly targeting NaV1.7 via prevention of CRMP2 SUMOylation. Here, our goal was to map the unique interface between CRMP2 and Ubc9, the E2 SUMO conjugating enzyme. Using computational and biophysical approaches, we demonstrate the enzyme/substrate nature of Ubc9/CRMP2 binding and identify hot spots on CRMP2 that may form the basis of future drug discovery campaigns disrupting the CRMP2-Ubc9 interaction to recapitulate allosteric regulation of NaV1.7 for pain relief.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.