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Sandbox454
From Proteopedia
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| - | == Pembrolizumab | + | == Pembrolizumab == |
<StructureSection load='5DK3' size='340' side='right' caption='Full-Length Crystal Structure of Pembrolizumab' scene=''> | <StructureSection load='5DK3' size='340' side='right' caption='Full-Length Crystal Structure of Pembrolizumab' scene=''> | ||
This is a default text for your page '''Sandbox454'''. Click above on '''edit this page''' to modify. Be careful with the < and > signs. | This is a default text for your page '''Sandbox454'''. Click above on '''edit this page''' to modify. Be careful with the < and > signs. | ||
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== Mechanism == | == Mechanism == | ||
| - | Pembrolizumab works as a PD-1 pathway inhibitor. As an inhibitor it targets the cell death of PD-1 and blocks the immune checkpoint pathway. PD-1 is expressed on the surface of t-cells. T-cells are main components of the immune response in the body. The main ligands that interact with this receptor are PD-L1 and PD-L2, which are expressed by some tumors and inhibit t-cell function when bound to PD-1 (http://link.springer.com/article/10.1007%2Fs40265-016-0543-x). Pembrolizumab has a very high affinity to PD-1, allowing it to block the interaction between PD-1 with PD-L1 and PD-L2. It antagonizes the interaction between PD-1 and its known ligands, re-activating anti-tumor immunity (http://www.tandfonline.com/doi/pdf/10.1080/17425255.2016.1216976?needAccess=true). The PD-1/PD-L1 interaction inhibits t-lymphocyte proliferation, releases cytokines and cytotoxicity, and exhausts tumor-specific t-cells. The inhibition of this pathway reverses the exhausted t-cell phenotype and normalizes the anti-tumor response. Pembrolizumab may cause inflammatory side effects. | + | Pembrolizumab works as a PD-1 pathway inhibitor. As an inhibitor it targets the cell death of PD-1 and blocks the immune checkpoint pathway. PD-1 is expressed on the surface of t-cells. T-cells are main components of the immune response in the body. The main ligands that interact with this receptor are PD-L1 and PD-L2, which are expressed by some tumors and inhibit t-cell function when bound to PD-1 (http://link.springer.com/article/10.1007%2Fs40265-016-0543-x). Pembrolizumab has a very high affinity to PD-1, allowing it to block the interaction between PD-1 with PD-L1 and PD-L2. It antagonizes the interaction between PD-1 and its known ligands, re-activating anti-tumor immunity (http://www.tandfonline.com/doi/pdf/10.1080/17425255.2016.1216976?needAccess=true). The PD-1/PD-L1 interaction inhibits t-lymphocyte proliferation, releases cytokines and cytotoxicity, and exhausts tumor-specific t-cells. The inhibition of this pathway reverses the exhausted t-cell phenotype and normalizes the anti-tumor response. Pembrolizumab may cause inflammatory side effects <ref>DOI: 10.1038/srep35297<ref/>. |
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This is a sample scene created with SAT to <scene name="/12/3456/Sample/1">color</scene> by Group, and another to make <scene name="/12/3456/Sample/2">a transparent representation</scene> of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes. | This is a sample scene created with SAT to <scene name="/12/3456/Sample/1">color</scene> by Group, and another to make <scene name="/12/3456/Sample/2">a transparent representation</scene> of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes. | ||
Revision as of 19:08, 11 November 2016
Pembrolizumab
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References
- ↑ Hanson, R. M., Prilusky, J., Renjian, Z., Nakane, T. and Sussman, J. L. (2013), JSmol and the Next-Generation Web-Based Representation of 3D Molecular Structure as Applied to Proteopedia. Isr. J. Chem., 53:207-216. doi:http://dx.doi.org/10.1002/ijch.201300024
- ↑ Herraez A. Biomolecules in the computer: Jmol to the rescue. Biochem Mol Biol Educ. 2006 Jul;34(4):255-61. doi: 10.1002/bmb.2006.494034042644. PMID:21638687 doi:10.1002/bmb.2006.494034042644
- ↑ Longoria TC, Tewari KS. Evaluation of the pharmacokinetics and metabolism of pembrolizumab in the treatment of melanoma. Expert Opin Drug Metab Toxicol. 2016 Oct;12(10):1247-53. doi:, 10.1080/17425255.2016.1216976. Epub 2016 Aug 16. PMID:27485741 doi:http://dx.doi.org/10.1080/17425255.2016.1216976
- ↑ doi: https://dx.doi.org/10.1038/srep35297<ref></ref>.==PemFab/PD-1Interaction====PemFv/PD-1Interaction==TheFvfragmentofpembrolizumab(PemFv)canformacomplexwiththeextracellulardomain(ECD)ofPD-1.BothPemFvandPD-1ECDcontaininterchaindisulfidebonds.PemFvinteractspredominantlyinthemajorgrooveofPD-1,whichisformedononesurfacebytheCC’FGantiparallelβ−sheetandtheBC,C’D,andFGloops.Thereare15directhydrogenbondsbetweentheresidues,15water-mediatedhydrogenbonds,2saltbridges,andmanyhydrophobicinteractions.Averylargesolvent-accessiblesurfaceareaof1,137Å2isburiedonPD-1ECDduetotheconvolutedinteraction.Thereareatotalof26PD-1ECDresiduesinvolvedintheinteractionwithPemFv,withresiduesinloopC’D(Pro84toGly90)andstrandC’(Gln75toLys78)playingamajorrole.ThesekeycomponentsofPD-1mainlyforminteractionsthroughsaltbridgesandhydrogenbondswithCRD-L3,CDR-H1,CDR-H2,CDR-H3ofpembrolizumab.ItisbeleivedthatthesugarchainsofPD-1havenophsyicalcontactwithpembrolizumabduetotheN-linkedglycosylatedresidues(Asn49,Asn58,Asn74,andAsn116)beinglocatedawayfromtheinteraface<ref>DOI</li></ol></ref>
