Investigation of the functional mechanism of small G protein Ran
Czigléczki Janka Zsófia
Gyógyszertudományok és Egészségügyi Technológiák Tagozat
Dr. Zelkó Romána
Semmelweis egyetem, Elméleti és Orvostudományi Központ, Hevesy György előadóterem
2026-05-27 14:00:00
Modern Trends in Pharmaceutical Scientific Research
Dr. Antal István
Dr. Balog Erika
Dr. Karancsiné Dr. Menyhárd Dóra
Dr. Czajlik András
Dr. Zelkó Romána
Dr. Balogh Balázs
Dr. Oláh Julianna
Molecular dynamics (MD) simulations offer an effective approach to study the conformational dynamics of small GTPases. In the present work, we investigated the nucleotide-dependent conformational dynamics of Ran, with a particular focus on the C-terminal region and the molecular mechanism underlying switch I opening by MD and aMDeNM simulations. Our results reveal pronounced nucleotide-dependent differences in Ran dynamics. In the GTP-bound state, the C-terminus exhibits substantially higher flexibility than in the GDP-bound form. These features suggest that Ran requires enhanced conformational plasticity in its active state, consistent with its role in nucleocytoplasmic transport.
Across all simulations, a conserved anchoring interaction between the N-terminal segment of the C-terminus and the α5-β2 interface of the G-domain was identified, providing a structural explanation for the frequent disorder of distal C-terminal residues in RanGTP crystal structures.
In addition, this study elucidates the molecular basis of switch I opening in RanGTP. Disruption of Mg²⁺ coordination alone induces only a partially open switch I conformation corresponding to the state 1 conformation described for Ras proteins, an open, effector-nonbinding state. A full transition to the RanGDP-like, fully open switch I conformation requires coordinated disruption of both Mg²⁺ coordination and the Phe35-GTP-Lys152 stabilizing triad. Triad destabilization is initiated by reorientation of Lys152 toward Glu186, leading to formation of a Lys152-Glu186 salt bridge. Together, these findings define a two-step mechanism for switch I opening and provide a framework for understanding Ran’s unique conformational regulation.
