title: Structural basis for small molecule targeting of the programmed death ligand 1 (PD-L1).
abstract: Targeting the PD-1/PD-L1 immunologic checkpoint with monoclonal antibodies has provided unprecedented results in cancer treatment in the recent years. Development of chemical inhibitors for this pathway lags the antibody development because of insufficient structural information. The first nonpeptidic chemical inhibitors that target the PD-1/PD-L1 interaction have only been recently disclosed by Bristol-Myers Squibb. Here, we show that these small-molecule compounds bind directly to PD-L1 and that they potently block PD-1 binding. Structural studies reveal a dimeric protein complex with a single small molecule which stabilizes the dimer thus occluding the PD-1 interaction surface of PD-L1s. The small-molecule interaction "hot spots" on PD-L1 surfaces suggest approaches for the PD-1/PD-L1 antagonist drug discovery.
authors.affiliation: Malopolska Centre of Biotechnology, Jagiellonian University, Gronostajowa, Krakow, Poland.|Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Gronostajowa, Krakow, Poland.
authors.forename: Krzysztof M
authors.initials: KM
authors.lastname: Zak
authors.affiliation: Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Gronostajowa, Krakow, Poland.
authors.forename: Przemyslaw
authors.initials: P
authors.lastname: Grudnik
authors.affiliation: Department of Organic Chemistry, Faculty of Chemistry, Jagiellonian University, Ingardena, Krakow, Poland.
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Guzik
authors.affiliation: Malopolska Centre of Biotechnology, Jagiellonian University, Gronostajowa, Krakow, Poland.|Department of Organic Chemistry, Faculty of Chemistry, Jagiellonian University, Ingardena, Krakow, Poland.
authors.forename: Bartosz J
authors.initials: BJ
authors.lastname: Zieba
authors.affiliation: Department of Organic Chemistry, Faculty of Chemistry, Jagiellonian University, Ingardena, Krakow, Poland.
authors.forename: Bogdan
authors.initials: B
authors.lastname: Musielak
authors.affiliation: Department for Drug Design, University of Groningen, A. Deusinglaan , Groningen, The Netherlands.
authors.forename: Alexander
authors.initials: A
authors.lastname: Dömling
authors.affiliation: Malopolska Centre of Biotechnology, Jagiellonian University, Gronostajowa, Krakow, Poland.|Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Gronostajowa, Krakow, Poland.
authors.forename: Grzegorz
authors.initials: G
authors.lastname: Dubin
authors.affiliation: Malopolska Centre of Biotechnology, Jagiellonian University, Gronostajowa, Krakow, Poland.|Department of Organic Chemistry, Faculty of Chemistry, Jagiellonian University, Ingardena, Krakow, Poland.|Max Planck Institute for Biochemistry, Am Klopferspitz, Martinsried, Germany.
authors.forename: Tad A
authors.initials: TA
authors.lastname: Holak
mesh_terms: D060890:B7-H1 Antigen / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism; D018360:Crystallography, X-Ray; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D015394:Molecular Structure; D061026:Programmed Cell Death 1 Receptor / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D000072417:Protein Domains; D015398:Signal Transduction / Q000187:drug effects; D054852:Small Molecule Libraries / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology
chemical_list: D060890:B7-H1 Antigen; C423236:CD274 protein, human; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D054852:Small Molecule Libraries
keywords: X-ray structure; checkpoint inhibitor; immunotherapy; small molecule