PhD Scientific Days 2024

Poster Session R - Pharmaceutical Sciences and Health Technologies 2.

Structural simulation study of the CRM1-RanGTP interactions

Text of the abstract

As a member of the Ras superfamily of small GTPases, Ran (Ras-related Nuclear protein) is the main regulator of the nucleo-cytoplasmic transport through the nuclear core complex. It functions as a molecular switch cycling between the GDP-bound inactive or “off” and GTP-bound active or “on” state. Since deregulation of Ran is linked to numerous cancers from the stage of cancer initiation to metastasis, understanding the complexity of its interaction, especially the regulatory mechanism, is critical for drug discovery. One of the partners in the nucleo-cytoplasmic transport is the export receptor CRM1 (chromosome region maintenance 1). CRM1 cooperatively binds RanGTP and cargo in the nucleus. Ran consists of a globular (G) or GTP binding domain (residue 1–172) and a C-terminal region (residue 173–216). The CRM1 structure contains 20 repetitive elements, so-called HEAT repeats, and in the transport complex, RanGTP is localized within the ring of CRM1 and bound by N- and C-terminal HEAT repeats. In the crystal structures of the GTP-bound active form of Ran complexed with CRM1, the structure of the C-terminal segment remains unresolved, indicating its large conformational flexibility. This movement could not have been followed either by experimental or simulation methods. Using simulations, our goal is to study potential conformational structures of the C-terminus of RanGTP in the CRM1-RanGTP complex and better understand the complex formation process and the transport complex conformational space.

Based on the results of molecular dynamics (MD) simulation, we present the human CRM1 protein conformational flexibility in free form, and for the first time in the literature, we were able to follow the conformational flexibility of the C-terminus of RanGTP in complex form. This conformational mapping allows us to envisage how the complex formation can occur and how the C-terminus of RanGTP can embrace other partners during the function of Ran.

This project was partially funded by the TKP2021-EGA-23 provided by the Ministry of Innovation and Technology of Hungary; by federal funds from the National Cancer Institute, National Institutes of Health, under contract HHSN261201500003I and by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research.