title: Simulation of the mutation F76del on the von Hippel-Lindau tumor suppressor protein: mechanism of the disease and implications for drug development.
abstract: 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.
authors.affiliation: Coordenação de Pesquisa Clínica e Incorporação Tecnológica, Instituto Nacional de Câncer - INCA, Rua André Cavalcanti, 37, Centro, 20231-050, Rio de Janeiro, RJ, Brazil. gabriel.sousa@inca.gov.br.
authors.forename: Gabriel
authors.initials: G
authors.lastname: Limaverde-Sousa
authors.forename: Ester de Andrade
authors.initials: Ede A
authors.lastname: Barreto
authors.forename: Carlos Gil
authors.initials: CG
authors.lastname: Ferreira
authors.forename: José Cláudio
authors.initials: JC
authors.lastname: Casali-da-Rocha
mesh_terms: D019295:Computational Biology / Q000379:methods*; D055808:Drug Discovery / Q000379:methods*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000737:chemistry / Q000378:metabolism; D056004:Molecular Dynamics Simulation; D009154:Mutation / Q000235:genetics; D011485:Protein Binding; D011487:Protein Conformation; D055550:Protein Stability; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D051794:Von Hippel-Lindau Tumor Suppressor Protein; C497446:VHL protein, human