Sandbox454
From Proteopedia
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In order for pembrolizumab to block PD-1, pembrolizumab forms a large, flat paratope (antigen-binding site) that can sustain PD-1’s large epitope (where antibody attaches on antigen). The induced interaction between pembrolizumab and PD-1 gives rise to a surface conformational change on PD-1. The new structure of PD-1 becomes a very shallow, “crescent”-like shape, in contrast to it’s flat conformation when bound to PD-L1 <ref>DOI: 10.1038/srep35297<ref/>. | In order for pembrolizumab to block PD-1, pembrolizumab forms a large, flat paratope (antigen-binding site) that can sustain PD-1’s large epitope (where antibody attaches on antigen). The induced interaction between pembrolizumab and PD-1 gives rise to a surface conformational change on PD-1. The new structure of PD-1 becomes a very shallow, “crescent”-like shape, in contrast to it’s flat conformation when bound to PD-L1 <ref>DOI: 10.1038/srep35297<ref/>. | ||
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| - | == PemFab/PD-1 Interaction == | ||
== PemFv/PD-1 Interaction == | == PemFv/PD-1 Interaction == | ||
Revision as of 19:10, 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>.==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>
