5J89

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

Summary for 5J89

• Entry DOI: 10.2210/pdb5j89/pdb
• Descriptor: Programmed cell death 1 ligand 1, N-{2-[({2-methoxy-6-[(2-methyl[1,1'-biphenyl]-3-yl)methoxy]pyridin-3-yl}methyl)amino]ethyl}acetamide, 1,2-ETHANEDIOL, ... (4 entities in total)
• Functional Keywords: pd-l1, programmed cell death 1 ligand 1, cell cycle, 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: 67838.12

Authors

Zak, K.M.,Grudnik, P.,Guzik, K.,Zieba, B.J.,Musielak, B.,Doemling, P.,Dubin, G.,Holak, T.A. (deposition date: 2016-04-07, release date: 2016-04-27, Last modification date: 2024-11-13)

Primary citation

Zak, K.M.,Grudnik, P.,Guzik, K.,Zieba, B.J.,Musielak, B.,Domling, A.,Dubin, G.,Holak, T.A.
Structural basis for small molecule targeting of the programmed death ligand 1 (PD-L1).
Oncotarget, 7:30323-30335, 2016

PubMed 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.

PubMed: 27083005
DOI: 10.18632/oncotarget.8730

Experimental method

X-RAY DIFFRACTION (2.2 Å)