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8F0Q

Structure of VSD4-NaV1.7-NaVPas channel chimera bound to the acylsulfonamide inhibitor GDC-0310

Summary for 8F0Q
Entry DOI10.2210/pdb8f0q/pdb
EMDB information28777
DescriptorSodium channel protein PaFPC1,Sodium channel protein type 9 subunit alpha chimera, beta-D-mannopyranose-(1-3)-beta-D-mannopyranose-(1-3)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-3)-2-acetamido-2-deoxy-beta-D-glucopyranose, beta-D-mannopyranose, ... (8 entities in total)
Functional Keywordsion channel, small molecule, inhibitor, membrane protein-inhibitor complex, membrane protein/inhibitor
Biological sourceHomo sapiens (human)
More
Total number of polymer chains1
Total formula weight190603.53
Authors
Primary citationKschonsak, 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
Cited by
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
PDB entries with the same primary citation
Experimental method
ELECTRON MICROSCOPY (2.5 Å)
Structure validation

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