5B8C

High resolution structure of the human PD-1 in complex with pembrolizumab Fv

Summary for 5B8C

• Entry DOI: 10.2210/pdb5b8c/pdb
• Descriptor: Pembrolizumab light chain variable region (PemVL), Pembrolizumab heavy chain variable region (PemVH), Programmed cell death protein 1, ... (4 entities in total)
• Functional Keywords: antibody, immune system
• Biological source: Homo sapiens; More
• Cellular location: Membrane; Single-pass type I membrane protein: Q15116
• Total number of polymer chains: 12
• Total formula weight: 168002.49

Authors

Horita, S.,Shimamura, T.,Iwata, S.,Nomura, N. (deposition date: 2016-06-14, release date: 2016-10-26, Last modification date: 2024-11-20)

Primary citation

Horita, S.,Nomura, Y.,Sato, Y.,Shimamura, T.,Iwata, S.,Nomura, N.
High-resolution crystal structure of the therapeutic antibody pembrolizumab bound to the human PD-1
Sci Rep, 6:35297-35297, 2016

PubMed Abstract: Pembrolizumab is an FDA-approved therapeutic antibody that targets the programmed cell death-1 (PD-1) to block the immune checkpoint pathway for the treatment of various types of cancer. It receives remarkable attention due to the high degree of efficacy. Very recently, the crystal structure of the Fab fragment of pembrolizumab (PemFab) in complex with the extracellular domain of human PD-1 (PD-1) was reported at a resolution of 2.9 Å. However, this relatively low-resolution structural data fails to provide sufficient information on interfacial water molecules at the binding interface that substantially contribute to affinity and specificity between the therapeutic antibody and target. Here, we present the independently determined crystal structure of the Fv fragment of pembrolizumab (PemFv) in complex with the PD-1 at a resolution of 2.15 Å. This high-resolution structure allows the accurate mapping of the interaction including water-mediated hydrogen bonds and provides, for the first time, a coherent explanation of PD-1 antagonism by pembrolizumab. Our structural data also provides new insights into the rational design of improved anti-PD-1 therapeutics.

PubMed: 27734966
DOI: 10.1038/srep35297

Experimental method

X-RAY DIFFRACTION (2.146 Å)