title: The inhibition mechanism of human 20S proteasomes enables next-generation inhibitor design.
abstract: The proteasome is a validated target for anticancer therapy, and proteasome inhibition is employed in the clinic for the treatment of tumors and hematological malignancies. Here, we describe crystal structures of the native human 20S proteasome and its complexes with inhibitors, which either are drugs approved for cancer treatment or are in clinical trials. The structure of the native human 20S proteasome was determined at an unprecedented resolution of 1.8 angstroms. Additionally, six inhibitor-proteasome complex structures were elucidated at resolutions between 1.9 and 2.1 angstroms. Collectively, the high-resolution structures provide new insights into the catalytic mechanisms of inhibition and necessitate a revised description of the proteasome active site. Knowledge about inhibition mechanisms provides insights into peptide hydrolysis and can guide strategies for the development of next-generation proteasome-based cancer therapeutics.
authors: Department of Structural Dynamics, Max Planck Institut für biophysikalische Chemie, Am Fassberg 11, D-37077 Göttingen, Germany.
authors: Jil
authors: J
authors: Schrader
authors: Department of Structural Dynamics, Max Planck Institut für biophysikalische Chemie, Am Fassberg 11, D-37077 Göttingen, Germany.
authors: Fabian
authors: F
authors: Henneberg
authors: Institut für Physikalische Chemie, Georg-August-Universität, Tamannstrasse 6, D-37077 Göttingen, Germany.
authors: Ricardo A
authors: RA
authors: Mata
authors: Göttinger Zentrum für Molekulare Biowissenschaften und Schwann-Schleiden-Forschungszentrum, Georg-August-Universität Göttingen, Julia-Lermontowa-Weg 3, D-37077 Göttingen, Germany.
authors: Kai
authors: K
authors: Tittmann
authors: European Molecular Biology Laboratory (EMBL), Hamburg Outstation c/o Deutsches Elektronen Synchrotron (DESY), Notkestrasse 85, D-22603 Hamburg, Germany.
authors: Thomas R
authors: TR
authors: Schneider
authors: Department of Structural Dynamics, Max Planck Institut für biophysikalische Chemie, Am Fassberg 11, D-37077 Göttingen, Germany.
authors: Holger
authors: H
authors: Stark
authors: European Molecular Biology Laboratory (EMBL), Hamburg Outstation c/o Deutsches Elektronen Synchrotron (DESY), Notkestrasse 85, D-22603 Hamburg, Germany. ashwin.chari@mpibpc.mpg.de gleb@embl-hamburg.de.
authors: Gleb
authors: G
authors: Bourenkov
authors: Department of Structural Dynamics, Max Planck Institut für biophysikalische Chemie, Am Fassberg 11, D-37077 Göttingen, Germany. ashwin.chari@mpibpc.mpg.de gleb@embl-hamburg.de.
authors: Ashwin
authors: A
authors: Chari
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D055162:Biocatalysis / Q000187:drug effects; D001896:Boron Compounds / Q000737:chemistry / Q000494:pharmacology; D001897:Boronic Acids / Q000737:chemistry / Q000494:pharmacology; D000069286:Bortezomib / Q000737:chemistry / Q000494:pharmacology; D020134:Catalytic Domain / Q000187:drug effects; D018360:Crystallography, X-Ray; D015195:Drug Design; D005998:Glycine / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D046988:Proteasome Endopeptidase Complex / Q000737:chemistry* / Q000648:ultrastructure; D061988:Proteasome Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D011487:Protein Conformation; D013912:Threonine / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D001896:Boron Compounds; D001897:Boronic Acids; D061988:Proteasome Inhibitors; D013912:Threonine; D000069286:Bortezomib; C527966:delanzomib; C548400:ixazomib; D046988:Proteasome Endopeptidase Complex; D005998:Glycine