Joint Research Group Macromolecular Crystallography
Structure of the month - April 2014
Nature (2014) 13181.
MTH1 inhibition eradicates cancer by preventing sanitation of the dNTP pool
Helge Gada, Tobias Koolmeistera, Ann-Sofie Jemtha, Saeed Eshtada, Sylvain A. Jacquesa, Cecilia E. Ströma, Linda M. Svenssonb, Niklas Schultza, Thomas Lundbäcka,c, Berglind Osk Einarsdottird, Aljona Salehe, Camilla Göktürka, Pawel Baranczewskia,f, Richard Svenssonc,f, Ronnie P.-A. Berntssonb, Robert Gustafssonb, Kia Strömberga, Kumar Sanjiva, Marie-Caroline Jacques-Cordonniera, Matthieu Desrosesa, Anna-Lena Gustavssona,c, Roger Olofssond, Fredrik Johanssong, Evert J. Homana, Olga Losevaa, Lars Bräutigama, Lars Johanssona,c, Andreas Höglunda, Anna Hagenkorta, Therese Phama, Mikael Altuna, Fabienne Z. Gaugaza,f, Svante Vikingssona,h, Bastiaan Eversa, Martin Henrikssona, Karl S. A. Vallina, Olov A. Wallnera, Lars G. J. Hammarströma,c, Elisee Wiitaa, Ingrid Almlöfa, Christina Kalderéna, Hanna Axelssona,c, Tatjana Djureinovicg, Jordi Carreras Puigverta, Maria Häggbladi, Fredrik Jeppssona, Ulf Martensi, Cecilia Lundina, Bo Lundgreni, Ingrid Granellie, Annika Jenmalm Jensena,c, Per Arturssonc,f, Jonas A. Nilssond, Pål Stenmarkb*, Martin Scobiea, Ulrika Warpman Berglunda & Thomas Helledaya
a Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, S-171 21 Stockholm, Sweden
b Department of Biochemistry and Biophysics, Stockholm University, S-106 91 Stockholm, Sweden
c Chemical Biology Consortium Sweden, Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, S-171 21 Stockholm, Sweden
d Sahlgrenska Translational Melanoma Group, Sahlgrenska Cancer Center, Department of Surgery, University of Gothenburg and Sahlgrenska University Hospital, S-405 30 Gothenburg, Sweden
e Department of Analytical Chemistry, Stockholm University, S-106 91 Stockholm, Sweden
f Uppsala University Drug Optimization and Pharmaceutical Profiling Platform, Department of Pharmacy, Uppsala University, S-751 23 Uppsala, Sweden
g Department of Genetics, Microbiology and Toxicology, Stockholm University, S-106 91 Stockholm, Sweden
h Clinical Pharmacology, Department of Medical and Health Sciences, Linköping University, S-58185 Linköping, Sweden
i Science for Life Laboratory, RNAi Cell Screening Facility, Department of Biochemistry and Biophysics, Stockholm University, S-106 91 Stockholm, Sweden
* Corresponding author: Pål Stenmark, Department of Biochemistry and Biophysics, Stockholm University, S-106 91 Stockholm, Sweden
E-mail: stenmark@db.su.se
Phone: +46(0)8-163729
Abstract
A team of researchers from five Swedish universities have identified a new way of treating cancer. The concept is presented in the journal Nature and is based on inhibiting a specific enzyme called MTH1, which cancer cells, unlike normal cells, require for survival. Without this enzyme, oxidized nucleotides are incorporated into DNA, resulting in lethal DNA double-strand breaks in cancer cells. The research group at Stockholm University has determined the structure of human MTH1 in complex with several key inhibitors. The detailed studies of how different molecules bind MTH1 has been essential to guide the development of efficient inhibitors and will now be used to develop these inhibitors into drugs.