9SNU
TKD of human Muscle Specific Kinase (MuSK) S752D mutant
Summary for 9SNU
| Entry DOI | 10.2210/pdb9snu/pdb |
| Related | 9SN0 |
| Descriptor | Muscle, skeletal receptor tyrosine-protein kinase (2 entities in total) |
| Functional Keywords | tyrosine kinase domain, neuromuscular junction, receptor tyrosine kinase, phosphorylation, transferase |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 1 |
| Total formula weight | 39958.93 |
| Authors | Proemer, J.J.,Murphy, J.W.,Lemmon, M.A.,Tsutsui, Y.,Herbst, R. (deposition date: 2025-09-11, release date: 2026-07-15) |
| Primary citation | Promer, J.J.,Murphy, J.W.,Lemmon, M.A.,Tsutsui, Y.,Herbst, R. An S752D activation loop mutation dynamically primes Muscle-Specific Kinase for activation. Biochem.J., 483:1221-1235, 2026 Cited by PubMed Abstract: Muscle-Specific Kinase (MuSK) is a receptor tyrosine kinase essential for neuromuscular junction (NMJ) formation and maintenance, yet its regulation remains poorly understood. Crystallographic studies of wild-type MuSK revealed an autoinhibited conformation with tyrosines in the activation loop (A-loop) anchored within the catalytic cleft to stabilize the closed, inactive conformation. We showed previously that additional phosphorylation of an A-loop serine may 'prime' MuSK for activation to sensitize it to ligand(s) in certain settings. Here, we employed crystallography, biochemical assays, and hydrogen-deuterium exchange and mass spectrometry (HDX-MS) to test this hypothesis. We found that introducing a phosphomimetic S752D mutation disrupts autoinhibitory A-loop interactions to increase ATP-binding affinity and catalytic turnover. Using HDX-MS, we further observed that the S752D mutation increases A-loop structural flexibility to relieve autoinhibition. The S752D mutation also stabilizes the juxtamembrane NPXY motif region, a docking site for the adaptor Dok7, possibly priming MuSK for downstream signaling. Together, these findings reveal dynamic transitions that underlie relief of MuSK autoinhibition and provide a mechanistic framework for understanding MuSK activation at the NMJ. PubMed: 42240394DOI: 10.1042/BCJ20260159 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.62 Å) |
Structure validation
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