title: Molecular model of hexokinase binding to the outer mitochondrial membrane porin (VDAC1): Implication for the design of new cancer therapies.
abstract: A key feature of many cancers is the capacity and the propensity to metabolize glucose to lactic acid at a very high rate even in the presence of oxygen. This characteristic was first discovered in 1924 by Otto Heinrich Warburg. Hexokinase, the first enzyme in the glycolytic pathway, not only improves the cell's energy supply in malignant cells, but also protects cancer cells against apoptosis through direct interaction with mitochondria and with the Voltage Dependent Anion Channel 1 (VDAC1). The rupture of HK:VDAC1 protein complex provides a therapeutic opportunity, as this association appears to protect tumor cells from mitochondrial outer membrane permeabilization, an event that marks the point of no return in multiple pathways leading to cell death. In the absence of a crystallographic structure and in order to perform an in silico screening of possible small molecules able to inhibit the protein association, we are presenting a computational model of HK-I:VDAC1 complex. It appears as evident how the first 15 N-terminal residues of HK-I interact with the inner part of the barrel of VDAC1 and not with the outside walls, within the mitochondrial membrane as previously believed. This finding is in agreement with the existence of a secondary ATP binding site in the same N-terminal region of HK-I which seems to have a crucial role in HK-I interaction with VDAC1. This evidence appears to be in accord also with the high levels of ATP that are found in cancer cells. Eventually such arrangements may contribute to stabilize the tertiary structure of VDAC1 while shielding from pro-apoptotic factor binding, protecting in a synergic way the tumoral cell from programmed death.
authors.affiliation: National Institute for Cancer Research (IST), L.go Rosanna Benzi 10, 16129 Genova, Italy. camillo.rosano@istge.it
authors.forename: Camillo
authors.initials: C
authors.lastname: Rosano
mesh_terms: D006593:Hexokinase / Q000737:chemistry* / Q000378:metabolism*; D006801:Humans; D051336:Mitochondrial Membranes / Q000737:chemistry* / Q000378:metabolism*; D008958:Models, Molecular; D008968:Molecular Conformation; D011485:Protein Binding; D020836:Protein Structure, Quaternary; D050995:Voltage-Dependent Anion Channel 1 / Q000737:chemistry* / Q000378:metabolism*
chemical_list: C494762:VDAC1 protein, human; D050995:Voltage-Dependent Anion Channel 1; D006593:Hexokinase