Unraveling the Binding Mode of TSC2–Rheb through Protein Docking and Simulations

TL;DR

This paper explores how TSC2 and Rheb proteins interact to regulate mTORC1, aiming to improve proteasome inhibitor therapy for multiple myeloma.

Contribution

The study proposes a novel computational model of the TSC2–Rheb complex to guide the development of new inhibitors.

Findings

A computational model of TSC2–Rheb binding was developed using PDB structures.

MD simulations confirmed the stability of the proposed TSC2–Rheb binding mode.

The findings provide a foundation for designing inhibitors to block TSC2–Rheb interaction.

Abstract

Proteasome inhibitors (PIs) constitute the first line
of therapy
for multiple myeloma (MM). Despite the impressive clinical efficacy,
MM remains fatal due to the development of drug resistance over time.
During MM progression, stress responses to hypoxia and PIs suppress
mammalian target of rapamycin complex 1 (mTORC1) activity by releasing
tuberous sclerosis complex 2 (TSC2), which deactivates Ras homologue
enriched in brain (Rheb), a crucial regulator of mTORC1. The efficacy
of PIs targeting MM is enhanced when mTORC1 is hyperactivated. We
thus propose that the inhibition of TSC2 will improve the efficacy
of PIs targeting MM. To the best of our knowledge, no cocrystallized
structure of the TSC2–Rheb complex has been reported. We therefore
developed a representative model using the individual structures of
TSC2 (PDB: 7DL2) and Rheb (PDB: 1XTS). Computational modeling involving an extensive protein–protein
docking consensus approach was performed to determine the putative
binding mode of TSC2–Rheb. The proposed docking poses were
refined, clustered, and evaluated by MD simulations to explore the
conformational dynamics and protein mobility, particularly at the
drug-binding interface of TSC2–Rheb. Our results agree with
the suggested binding mode of TSC2–Rheb previously reported
in the literature. The results reported herein establish a basis for
the development of new inhibitors blocking the binding of TSC2 and
Rheb, aiming to reinstate mTORC1 activation and facilitate improved
efficacy of PIs against multiple myeloma.

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