Exploring the structural basis of conformational heterogeneity and autoinhibition of human cGMP-specific protein kinase I? through computational modelling and molecular dynamics simulations.

ABSTRACT: Protein kinase I? (PKGI?) is a pivotal cyclic guanosine monophosphate (cGMP) signalling protein. Major steps related to the structural plasticity of PKGI? have been inferred but the structural aspects of the auto-inhibition and multidomain tertiary organization of human PKGI? in active and inactive form are not clear. Here we combine computational comparative modelling, protein-protein docking and molecular dynamics (MD) simulations to investigate structural details of the repressed state of the catalytic domain of PKGI?. Exploration of the potential inhibitory conformation of the auto-inhibitory domain (AI) within the catalytic cleft reveals that the pseudo-substrate motif binds with residues of the glycine rich loop and substrate-binding lobe. Dynamic changes as a result of coupling of the catalytic and AI domains are also investigated. The three-dimensional homodimeric models of PKGI? in the active and inactive state indicate that PKGI? in its inactive-state attains a compact globular structure where cyclic nucleotide binding (CNB-A/B) domains are buried, whereas the catalytic domains are inaccessible with their substrate-binding pockets facing the N-terminal of CNB-A. Contrary to this, the active-state model of PKGI? shows an extended conformation where CNB-A/B domains are slightly rearranged and the catalytic domains of homodimer flanking the C-terminal with their substrate binding lobes free to entrap downstream proteins. These findings are consistent with previously reported static images of the multidomain organization of PKGI?. Structural insights pertaining to the conformational heterogeneity and auto-inhibition of PKGI? provided in this study may help to understand the dynamics-driven effective regulation of PKGI?.

SUBMITTER: Maryam A 

PROVIDER: S-EPMC7334484 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature