• PDGFRβ kinase activity is regulated by multiple allosteric mechanisms, including dimerization of activated kinases, autoinhibition by the kinase insert, and dimerization of inactive kinase.
• These allosteric regulatory mechanisms are conserved across type III receptor tyrosine kinases, including CSF1R.
• Impaired allosteric regulation of CSF1R is linked to microglial dysfunction and neuronal demyelination in hereditary diffuse leukoencephalopathy with spheroids (HDLS).
• The findings provide a comprehensive framework for understanding the precise regulation of PDGFRβ and related receptors, with implications for therapeutic targeting.