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Title: High-resolution crystal structure of the therapeutic antibody pembrolizumab bound to the human PD-1
Authors: Horita, Shoichiro
Nomura, Yayoi
Sato, Yumi
Shimamura, Tatsuro  kyouindb  KAKEN_id
Iwata, So  kyouindb  KAKEN_id
Nomura, Norimichi  kyouindb  KAKEN_id
Author's alias: 野村, 紀通
Issue Date: 13-Oct-2016
Publisher: Springer Nature
Journal title: Scientific Reports
Volume: 6
Thesis number: 35297
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-1ECD) 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-1ECD 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.
Rights: This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit
DOI(Published Version): 10.1038/srep35297
PubMed ID: 27734966
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