5XXY

Crystal structure of PD-L1 complexed with atezolizumab fab at 2.9A

Summary for 5XXY

• Entry DOI: 10.2210/pdb5xxy/pdb
• Descriptor: heavy chain of atezolizumab fab, light chain of atezolizumab fab, Programmed cell death 1 ligand 1, ... (4 entities in total)
• Functional Keywords: pd-l1, atezolizumab, immune system
• Biological source: Homo sapiens; More
• 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: 3
• Total formula weight: 63268.73

Authors

Zhou, A.,Zhang, F. (deposition date: 2017-07-05, release date: 2017-09-20, Last modification date: 2024-11-20)

Primary citation

Zhang, F.,Qi, X.,Wang, X.,Wei, D.,Wu, J.,Feng, L.,Cai, H.,Wang, Y.,Zeng, N.,Xu, T.,Zhou, A.,Zheng, Y.
Structural basis of the therapeutic anti-PD-L1 antibody atezolizumab.
Oncotarget, 8:90215-90224, 2017

PubMed Abstract: Monoclonal antibodies targeting PD-1/PD-L1 signaling pathway have achieved unprecedented success in cancer treatment over the last few years. Atezolizumab is the first PD-L1 monoclonal antibody approved by US FDA for cancer therapy; however the molecular basis of atezolizumab in blocking PD-1/PD-L1 interaction is not fully understood. Here we have solved the crystal structure of PD-L1/atezolizumab complex at 2.9 angstrom resolution. The structure shows that atezolizumab binds the front beta-sheet of PD-L1 through three CDR loops from the heavy chain and one CDR loop from the light chain. The binding involves extensive hydrogen-bonding and hydrophobic interactions. Notably there are multiple aromatic residues from the CDR loops forming Pi-Pi stacking or cation-Pi interactions within the center of the binding interface and the buried surface area is more than 2000 Å, which is the largest amongst all the known PD-L1/antibody structures. Mutagenesis study revealed that two hot-spot residues (E58, R113) of PD-L1 contribute significantly to the binding of atezolizumab. The structure also shows that atezolizumab binds PD-L1 with a distinct heavy and light chain orientation and it blocks PD-1/PD-L1 interaction through competing with PD-1 for the same PD-L1 surface area. Taken together, the complex structure of PD-L1/atezolizumab solved here revealed the molecular mechanism of atezolizumab in immunotherapy and provides basis for future monoclonal antibody optimization and rational design of small chemical compounds targeting PD-L1 surface.

PubMed: 29163822
DOI: 10.18632/oncotarget.21652

Experimental method

X-RAY DIFFRACTION (2.9 Å)