Simulation of the mutation F76del on the von Hippel–Lindau tumor suppressor protein: Mechanism of the disease and implications for drug development
Article first published online: 26 OCT 2012
Copyright © 2012 Wiley Periodicals, Inc.
Proteins: Structure, Function, and Bioinformatics
Volume 81, Issue 2, pages 349–363, February 2013
How to Cite
Limaverde-Sousa, G., de Andrade Barreto, E., Ferreira, C. G. and Cláudio Casali-da-Rocha, J. (2013), Simulation of the mutation F76del on the von Hippel–Lindau tumor suppressor protein: Mechanism of the disease and implications for drug development. Proteins, 81: 349–363. doi: 10.1002/prot.24191
- Issue published online: 18 JAN 2013
- Article first published online: 26 OCT 2012
- Accepted manuscript online: 26 SEP 2012 05:57AM EST
- Manuscript Accepted: 19 SEP 2012
- Manuscript Revised: 8 SEP 2012
- Manuscript Received: 14 APR 2012
- Programa Nacional de Pós-Doutorado (CAPES/PNPD), Brazil. Grant Number: PNPD 02954/09-5.
- von Hippel–Lindau;
- drug development;
- molecular dynamics;
The von Hippel–Lindau tumor suppressor protein (pVHL) plays a central role in the oxygen-sensing pathway by regulating the degradation of the hypoxia-inducible factor (HIF-1α). The capture of HIF-1α by pVHL is regulated by an oxygen-dependent hydroxylation of a specific conserved prolyl residue. The VHL gene is mutated in the von Hippel–Lindau cancer predisposition syndrome, which is characterized by the development of highly vascularized tumors and is associated with constitutively high levels of HIF-1α. The disturbance of the dynamic coupling between HIF-1α and pVHL bearing the commonly found mutation F76del was experimentally confirmed but the mechanism of such complex disruption is still not clear. Performing unbiased molecular dynamics simulations, we show that the F76del mutation may enlarge the HIF binding pocket in pVHL and induce the formation of an internal cavity in the hydrophobic core of the β-domain, which can lead to a partial destabilization of the β-sheets S1, S4, and S7 and a consequent loss of hydrogen bonds with a conserved recognition motif in HIF. The newly formed cavity has a significant druggability score and may be a suitable target for stabilizing ligands. Studies of this nature may help to fill the information gap between genotype–phenotype correlations with details obtained at atomic level and provide basis for future development of drug candidates, such as pharmacological chaperones, with the specific aim of reverting the dysfunction of such pathological protein complexes found in patients with VHL. Proteins 2013. © 2012 Wiley Periodicals, Inc.