5NIU

Structure of human Programmed cell death 1 ligand 1 (PD-L1) with low molecular mass inhibitor

Summary for 5NIU

• Entry DOI: 10.2210/pdb5niu/pdb
• Descriptor: Programmed cell death 1 ligand 1, (2~{R})-2-[[2-[(3-cyanophenyl)methoxy]-4-[[3-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-methyl-phenyl]methoxy]-5-methyl-phenyl]methylamino]-3-oxidanyl-propanoic acid, 1,2-ETHANEDIOL, ... (4 entities in total)
• Functional Keywords: pd-l1, pd-1, immune checkpoint, immune system
• Biological source: Homo sapiens (Human)
• Cellular location: Isoform 1: Cell membrane ; Single-pass type I membrane protein . Isoform 2: Endomembrane system ; Single-pass type I membrane protein : Q9NZQ7
• Total number of polymer chains: 4
• Total formula weight: 60028.48

Authors

Zak, K.M.,Grudnik, P.,Skalniak, L.,Dubin, G.,Holak, T.A. (deposition date: 2017-03-27, release date: 2017-12-06, Last modification date: 2024-11-13)

Primary citation

Skalniak, L.,Zak, K.M.,Guzik, K.,Magiera, K.,Musielak, B.,Pachota, M.,Szelazek, B.,Kocik, J.,Grudnik, P.,Tomala, M.,Krzanik, S.,Pyrc, K.,Domling, A.,Dubin, G.,Holak, T.A.
Small-molecule inhibitors of PD-1/PD-L1 immune checkpoint alleviate the PD-L1-induced exhaustion of T-cells.
Oncotarget, 8:72167-72181, 2017

PubMed Abstract: Antibodies targeting the PD-1/PD-L1 immune checkpoint achieved spectacular success in anticancer therapy in the recent years. In contrast, no small molecules with cellular activity have been reported so far. Here we provide evidence that small molecules are capable of alleviating the PD-1/PD-L1 immune checkpoint-mediated exhaustion of Jurkat T-lymphocytes. The two optimized small-molecule inhibitors of the PD-1/PD-L1 interaction, BMS-1001 and BMS-1166, developed by Bristol-Myers Squibb, bind to human PD-L1 and block its interaction with PD-1, when tested on isolated proteins. The compounds present low toxicity towards tested cell lines and block the interaction of soluble PD-L1 with the cell surface-expressed PD-1. As a result, BMS-1001 and BMS-1166 alleviate the inhibitory effect of the soluble PD-L1 on the T-cell receptor-mediated activation of T-lymphocytes. Moreover, the compounds were effective in attenuating the inhibitory effect of the cell surface-associated PD-L1. We also determined the X-ray structures of the complexes of BMS-1001 and BMS-1166 with PD-L1, which revealed features that may be responsible for increased potency of the compounds compared to their predecessors. Further development may lead to the design of an anticancer therapy based on the orally delivered immune checkpoint inhibition.

PubMed: 29069777
DOI: 10.18632/oncotarget.20050

Experimental method

X-RAY DIFFRACTION (2.01 Å)