Local and distal changes in dynamics are caused by an L205R Cushing's syndrome mutant in PRKACA.

ABSTRACT: Cushing's syndrome (CS) is an abnormal condition characterized by elevated cortisol levels, often resulting from genetic alterations in the PRKACA gene, which encodes the catalytic subunit of cAMP-dependent protein kinase A (PKA-C). The most common CS mutation, L205R, lies at the P + 1 loop. Understanding how this mutation alters the internal allosteric network within PKA-C and changes nucleotide and substrate cooperativity is a major goal. Using molecular dynamics (MD) simulations and protein residue networks based on local spatial pattern (LSP) method, we compare crystal structures of wild-type PKA-C and L205R. Our findings indicate that L205R not only locally disrupts the P + 1 hydrophobic pocket, leading to the displacement of the P + 1-residue and altered substrate specificity,

SUBMITTER: Kalle A 

PROVIDER: S-EPMC12184650 | biostudies-literature | 2025 Jun

REPOSITORIES: biostudies-literature