8F0S

Structure of VSD4-NaV1.7-NaVPas channel chimera bound to the hybrid inhibitor GNE-9296

Summary for 8F0S

• Entry DOI: 10.2210/pdb8f0s/pdb
• EMDB information: 28779
• Descriptor: Sodium channel protein PaFPC1,Sodium channel protein type 9 subunit alpha chimera, Beta-diguetoxin-Dc1a, beta-D-mannopyranose-(1-3)-[beta-D-mannopyranose-(1-6)]beta-D-mannopyranose-(1-3)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-3)-2-acetamido-2-deoxy-beta-D-glucopyranose, ... (8 entities in total)
• Functional Keywords: ion channel, small molecule, inhibitor, membrane protein-inhibitor complex, membrane protein/inhibitor
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 2
• Total formula weight: 196743.09

Authors

Kschonsak, M.,Jao, C.C.,Arthur, C.P.,Rohou, A.L.,Bergeron, P.,Ortwine, D.,McKerall, S.J.,Hackos, D.H.,Deng, L.,Chen, J.,Sutherlin, D.,Dragovich, P.S.,Volgraf, M.,Wright, M.R.,Payandeh, J.,Ciferri, C.,Tellis, J.C. (deposition date: 2022-11-03, release date: 2023-04-12)

Primary citation

Kschonsak, M.,Jao, C.C.,Arthur, C.P.,Rohou, A.L.,Bergeron, P.,Ortwine, D.F.,McKerrall, S.J.,Hackos, D.H.,Deng, L.,Chen, J.,Li, T.,Dragovich, P.S.,Volgraf, M.,Wright, M.R.,Payandeh, J.,Ciferri, C.,Tellis, J.C.
Cryo-EM reveals an unprecedented binding site for Na V 1.7 inhibitors enabling rational design of potent hybrid inhibitors.
Elife, 12:-, 2023

PubMed Abstract: The voltage-gated sodium (Na) channel Na1.7 has been identified as a potential novel analgesic target due to its involvement in human pain syndromes. However, clinically available Na channel-blocking drugs are not selective among the nine Na channel subtypes, Na1.1-Na1.9. Moreover, the two currently known classes of Na1.7 subtype-selective inhibitors (aryl- and acylsulfonamides) have undesirable characteristics that may limit their development. To this point understanding of the structure-activity relationships of the acylsulfonamide class of Na1.7 inhibitors, exemplified by the clinical development candidate , has been based solely on a single co-crystal structure of an arylsulfonamide inhibitor bound to voltage-sensing domain 4 (VSD4). To advance inhibitor design targeting the Na1.7 channel, we pursued high-resolution ligand-bound Na1.7-VSD4 structures using cryogenic electron microscopy (cryo-EM). Here, we report that engages the Na1.7-VSD4 through an unexpected binding mode orthogonal to the arylsulfonamide inhibitor class binding pose, which identifies a previously unknown ligand binding site in Na channels. This finding enabled the design of a novel hybrid inhibitor series that bridges the aryl- and acylsulfonamide binding pockets and allows for the generation of molecules with substantially differentiated structures and properties. Overall, our study highlights the power of cryo-EM methods to pursue challenging drug targets using iterative and high-resolution structure-guided inhibitor design. This work also underscores an important role of the membrane bilayer in the optimization of selective Na channel modulators targeting VSD4.

PubMed: 36975198
DOI: 10.7554/eLife.84151

Experimental method

ELECTRON MICROSCOPY (3.1 Å)