6j14

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Complex structure of GY-14 and PD-1

Structural highlights

6j14 is a 3 chain structure with sequence from Homo sapiens and Mus musculus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 1.4Å
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

PDCD1_HUMAN Systemic lupus erythematosus;Multiple sclerosis. Systemic lupus erythematosus 2 (SLEB2) [MIM:605218: A chronic, relapsing, inflammatory, and often febrile multisystemic disorder of connective tissue, characterized principally by involvement of the skin, joints, kidneys and serosal membranes. It is of unknown etiology, but is thought to represent a failure of the regulatory mechanisms of the autoimmune system. The disease is marked by a wide range of system dysfunctions, an elevated erythrocyte sedimentation rate, and the formation of LE cells in the blood or bone marrow. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.[1]

Function

PDCD1_HUMAN Inhibitory cell surface receptor involved in the regulation of T-cell function during immunity and tolerance. Upon ligand binding, inhibits T-cell effector functions in an antigen-specific manner. Possible cell death inducer, in association with other factors.[2]

Publication Abstract from PubMed

Programmed cell death 1 (PD-1)/PD-1 ligand-1 (PD-L1)-blocking monoclonal antibodies (mAbs) have taken center stage for tumor immune checkpoint therapy. Identification of the "hotspots" on PD-1 for mAbs will help to develop next-generation oral deliverable agents with long-lasting efficacy. Here, we identified two PD-1-targeting mAbs, GY-5 and GY-14, with PD-1/PD-L1-blocking efficacy. Complex structural information revealed that both mAbs mainly bind to the FG loop of PD-1, which also contributes multiple interactions with PD-L1. The FG loop adopts substantially varied conformations upon binding to different mAbs, providing a novel targetable region for the development of PD-1-specific biologics and small chemical molecules. Glycosylation modifications of PD-1 could be observed in three of the four potential N-linked glycosylation sites. However, the binding of GY-5 and GY-14 to PD-1 was not affected by glycosylation. These findings broaden our understanding of the mechanism of anti-PD-1 mAbs and provide insight into the development of agents targeting PD-1.

The FG Loop of PD-1 Serves as a "Hotspot" for Therapeutic Monoclonal Antibodies in Tumor Immune Checkpoint Therapy.,Chen D, Tan S, Zhang H, Wang H, He W, Shi R, Tong Z, Zhu J, Cheng H, Gao S, Chai Y, Qi J, Xiao M, Yan J, Gao GF iScience. 2019 Apr 26;14:113-124. doi: 10.1016/j.isci.2019.03.017. Epub 2019 Mar , 21. PMID:30952089[3]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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Citations
7 reviews cite this structure
Revisiting the PD-1 pathway.
Patsoukis et al. (2020)
6 more
17 other articles
No citations found

See Also

References

  1. ↑ Prokunina L, Castillejo-Lopez C, Oberg F, Gunnarsson I, Berg L, Magnusson V, Brookes AJ, Tentler D, Kristjansdottir H, Grondal G, Bolstad AI, Svenungsson E, Lundberg I, Sturfelt G, Jonssen A, Truedsson L, Lima G, Alcocer-Varela J, Jonsson R, Gyllensten UB, Harley JB, Alarcon-Segovia D, Steinsson K, Alarcon-Riquelme ME. A regulatory polymorphism in PDCD1 is associated with susceptibility to systemic lupus erythematosus in humans. Nat Genet. 2002 Dec;32(4):666-9. Epub 2002 Oct 28. PMID:12402038 doi:10.1038/ng1020
  2. ↑ Fife BT, Pauken KE. The role of the PD-1 pathway in autoimmunity and peripheral tolerance. Ann N Y Acad Sci. 2011 Jan;1217:45-59. doi: 10.1111/j.1749-6632.2010.05919.x. PMID:21276005 doi:10.1111/j.1749-6632.2010.05919.x
  3. ↑ Chen D, Tan S, Zhang H, Wang H, He W, Shi R, Tong Z, Zhu J, Cheng H, Gao S, Chai Y, Qi J, Xiao M, Yan J, Gao GF. The FG Loop of PD-1 Serves as a "Hotspot" for Therapeutic Monoclonal Antibodies in Tumor Immune Checkpoint Therapy. iScience. 2019 Apr 26;14:113-124. doi: 10.1016/j.isci.2019.03.017. Epub 2019 Mar , 21. PMID:30952089 doi:http://dx.doi.org/10.1016/j.isci.2019.03.017

Contents


PDB ID 6j14

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OCA

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