Skip to main content
universidade lusófona

Projects

Studies on the human Pgp folding

PI Daniel dos Santos

CBIOS Team member

Patrícia Dias de Mendonça Rijo
From 2022 to 2023

Description

Overexpression of P-glycoprotein (Pgp/ABCB1) in cancer is a marker of overall poor chemotherapy response and prognosis. This computational project builds on previous studies lead by the PI and Co-PI on multidrug resistance (MDR) in cancer by using computational models and simulations for gaining information about the inner dynamics, structural features and drug-Pgp interaction and mode of action.

The human Pgp conformations deposited recently on the Protein Data Bank revealed a new inward facing conformation that may represent either the closing of a gate region or an artifact derived from lateral compression in a too small size nanodisc, used to stabilize the transporter. Using a simpler model, we have done preliminary investigations pointing for the presence of an artifact in the experimental protocol (DOI:10.1101/692988).

However, this hypothesis can only be tested and settled using molecular dynamics simulations at very long time scales with complete atomistic description of the biochemical system, impossible to match using in-house resources. Knowing if there is an artifact on the human structures or if this new structures correspond to a yet to be confirmed meta-stable intermediary state is of capital importance since further computational studies of Pgp can only produce reliable information when using Pgp structures representative of its correct native fold.

Outputs

    1. Bonito, C. A.; Ferreira, R. J.; Ferreira, M.-José. U.; Durães, F.; Sousa, E.; Gillet, J.-P.; Cordeiro, M. N. D. S.; dos Santos, D. J. V. A. Probing the Allosteric Modulation of P-Glycoprotein: A Medicinal Chemistry Approach Toward the Identification of Noncompetitive P-Gp Inhibitors. ACS Omega 2023, 8 (12), 11281–11287. https://doi.org/10.1021/acsomega.2c08273.
    2. Bonito, C. A.; Ferreira, R. J.; Ferreira, M.-J. U.; Gillet, J.-P.; Cordeiro, M. N. D. S.; dos Santos, D. J. V. A. Long-Range Communication between Transmembrane- and Nucleotide-Binding Domains Does Not Depend on Drug Binding to Mutant P-Glycoprotein. Journal of Biomolecular Structure and Dynamics 2023, 0 (0), 1–10. https://doi.org/10.1080/07391102.2023.2181633 .

Funding

FCT Advanced Computing Project, reference 2021.09821.CPCA