6PV9

Human PD-L1 bound to a macrocyclic peptide which blocks the PD-1/PD-L1 interaction

Summary for 6PV9

• Entry DOI: 10.2210/pdb6pv9/pdb
• Descriptor: Programmed cell death 1 ligand 1, macrocyclic peptide (3 entities in total)
• Functional Keywords: pd-l1 pd-1 cancer immunotherapy checkpoint inhibitor, immune system
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 2
• Total formula weight: 27296.09

Authors

Appleby, T.C.,Lad, L.,Gross, M.L. (deposition date: 2019-07-19, release date: 2020-01-01, Last modification date: 2024-04-03)

Primary citation

Niu, B.,Appleby, T.C.,Wang, R.,Morar, M.,Voight, J.,Villasenor, A.G.,Clancy, S.,Wise, S.,Belzile, J.P.,Papalia, G.,Wong, M.,Brendza, K.M.,Lad, L.,Gross, M.L.
Protein Footprinting and X-ray Crystallography Reveal the Interaction of PD-L1 and a Macrocyclic Peptide.
Biochemistry, 59:541-551, 2020

PubMed Abstract: Blocking interactions between PD-1 and PD-L1 opens a new era of cancer treatment involving immunity modulation. Although most immunotherapies use monoclonal antibodies, small-molecule inhibitors offer advantages. To facilitate development of small-molecule therapeutics, we implemented a rapid approach to characterize the binding interfaces of small-molecule inhibitors with PD-L1. We determined its interaction with a synthetic macrocyclic peptide by using two mass spectrometry-based approaches, hydrogen-deuterium exchange and fast photochemical oxidation of proteins (FPOP), and corroborated the findings with our X-ray structure of the PD-L1/macrocycle complex. Although all three approaches show that the macrocycle binds directly to PD-L1 over the regions of residues 46-87 and 114-125, the two protein footprinting approaches show additional binding at the N-terminus of PD-L1, and FPOP reveals some critical binding residues. The outcomes not only show the binding regions but also demonstrate the utility of MS-based footprinting in probing protein/ligand inhibitory interactions in cancer immunotherapy.

PubMed: 31841311
DOI: 10.1021/acs.biochem.9b00822

Experimental method

X-RAY DIFFRACTION (2 Å)