5IUS

Crystal structure of human PD-L1 in complex with high affinity PD-1 mutant

Summary for 5IUS

• Entry DOI: 10.2210/pdb5ius/pdb
• Descriptor: Programmed cell death protein 1, Programmed cell death 1 ligand 1, CHLORIDE ION, ... (4 entities in total)
• Functional Keywords: immune checkpoint, tumor surveillance, cancer, receptor, immune system
• Biological source: Homo sapiens (Human); More
• Cellular location: Membrane; Single-pass type I membrane protein: Q15116; 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: 79927.22

Authors

Pascolutti, R.,Sun, X.,Kao, J.,Maute, R.,Ring, A.M.,Bowman, G.R.,Kruse, A.C. (deposition date: 2016-03-18, release date: 2016-09-28, Last modification date: 2024-11-13)

Primary citation

Pascolutti, R.,Sun, X.,Kao, J.,Maute, R.L.,Ring, A.M.,Bowman, G.R.,Kruse, A.C.
Structure and Dynamics of PD-L1 and an Ultra-High-Affinity PD-1 Receptor Mutant.
Structure, 24:1719-1728, 2016

PubMed Abstract: The immune checkpoint receptor PD-1 and its ligand, PD-L1, have emerged as key regulators of anti-tumor immunity in humans. Recently, we reported an ultra-high-affinity PD-1 mutant, termed high-affinity consensus (HAC) PD-1, which shows superior therapeutic efficacy in mice compared with antibodies. However, the molecular details underlying the action of this agent remain incompletely understood, and a molecular view of PD-1/PD-L1 interactions in general is only beginning to emerge. Here, we report the structure of HAC PD-1 in complex with PD-L1, showing that it binds PD-L1 using a unique set of polar interactions. Biophysical studies and long-timescale molecular dynamics experiments reveal the mechanisms by which ten point mutations confer a 35,000-fold enhancement in binding affinity, and offer atomic-scale views of the role of conformational dynamics in PD-1/PD-L1 interactions. Finally, we show that the HAC PD-1 exhibits pH-dependent affinity, with pseudo-irreversible binding in a low pH setting akin to the tumor microenvironment.

PubMed: 27618663
DOI: 10.1016/j.str.2016.06.026

Experimental method

X-RAY DIFFRACTION (2.889 Å)