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Published on: November 29, 2013
Unraveling the Molecular Inhibition and Conformational Changes of Hsp70 and Hsc70 Induced by VER-155008, a
Maria Caroline Barbosa da Silva1, Carlos Gefferson Silva Falabelo2, Elvis Santos Leonardo3
1Laboratório de Simulação Computacional, Instituto de Biodiversidade, Universidade Federal do Oeste do Pará, Rua Vera Paz, Salé s/n, 68040-255 Santarém, Pará, Brazil.
Abstract:
The heat shock protein 70 kDa (Hsp70) is critical for the survival of cancer cells, playing a role in developing chemotherapy resistance, since it inhibits apoptosis of these cells and ensures their survival in stressful environments. Due to its structural similarity with heat shock cognate 70 kDa (Hsc70), the design of new selective Hsp70 inhibitors presents significant challenges. Previous studies have reported that the molecule VER-155008 functions as a nonselective inhibitor of Hsp70 by binding to the nucleotide-binding domain of both proteins, thereby acting as a competitive inhibitor of adenosine triphosphate (ATP) binding. In the present study, molecular dynamics (MD) simulations and free energy landscape (FEL) analysis were used to investigate the conformational dynamics of Hsp70 and Hsc70 with the competitive ATPase inhibitor VER-155008, revealing its binding mechanism and its role in inducing a half-open conformation that inhibits ATP binding. Our findings highlight key residues Ser275, Lys271, and Glu268 involved in the stabilization of the inhibitor binding and some conformational states in both proteins due to the inhibitor binding, explaining molecular characteristics that could be used to develop new selective inhibitors at the nucleotide binding site of Hsp70, thus aiming to advance the development of targeted therapies in cancer treatment.
Insights
Heat shock protein 70 kDa (Hsp70) aids cancer cell survival and chemotherapy resistance. This study reveals how VER-155008 inhibits Hsp70 by inducing a half-open conformation, offering insights for developing targeted cancer therapies.
Area of Science:
- Biochemistry
- Molecular Biology
- Cancer Research
Background:
- Heat shock protein 70 kDa (Hsp70) is crucial for cancer cell survival and chemotherapy resistance by inhibiting apoptosis.
- Hsp70's structural similarity to Hsc70 complicates the development of selective Hsp70 inhibitors.
- VER-155008 is a known nonselective Hsp70 inhibitor that competitively inhibits adenosine triphosphate (ATP) binding.
Purpose of the Study:
- To investigate the conformational dynamics of Hsp70 and Hsc70 in the presence of the inhibitor VER-155008.
- To elucidate the binding mechanism of VER-155008 and its effect on ATP binding.
- To identify molecular characteristics for developing novel, selective Hsp70 inhibitors for cancer therapy.
Main Methods:
- Molecular dynamics (MD) simulations.
- Free energy landscape (FEL) analysis.
Main Results:
- VER-155008 induces a half-open conformation in Hsp70 and Hsc70, inhibiting ATP binding.
- Key residues (Ser275, Lys271, Glu268) were identified as crucial for stabilizing inhibitor binding and conformational states.
- The study provides a molecular understanding of VER-155008's inhibitory action.
Conclusions:
- The findings elucidate VER-155008's mechanism of action on Hsp70 and Hsc70.
- Identified molecular characteristics can guide the design of selective Hsp70 inhibitors.
- This research advances the development of targeted cancer therapies by focusing on Hsp70 inhibition.
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