Sandbox454
From Proteopedia
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== PemFab/PD-1 Interaction == | == PemFab/PD-1 Interaction == | ||
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== PemFv/PD-1 Interaction == | == PemFv/PD-1 Interaction == | ||
The Fv fragment of pembrolizumab (PemFv) can form a complex with the extracellular domain (ECD) of PD-1. Both PemFv and PD-1ECD contain interchain disulfide bonds. PemFv interacts predominantly in the major groove of PD-1, which is formed on one surface by the CC’FG antiparallel β−sheet and the BC, C’D, and FG loops. There are 15 direct hydrogen bonds between the residues, 15 water-mediated hydrogen bonds, 2 salt bridges, and many hydrophobic interactions. A very large solvent-accessible surface area of 1,137Å2 is buried on PD-1ECD due to the convoluted interaction. There are a total of 26 PD-1ECD residues involved in the interaction with PemFv, with residues in loop C’D (Pro84 to Gly90) and strand C’ (Gln75 to Lys 78) playing a major role. These key components of PD-1 mainly form interactions through salt bridges and hydrogen bonds with CRD-L3, CDR-H1, CDR-H2, CDR-H3 of pembrolizumab. It is beleived that the sugar chains of PD-1 have no phsyical contact with pembrolizumab due to the N-linked glycosylated residues (Asn49, Asn58, Asn74, and Asn116) being located away from the interaface <ref>DOI: 10.1038/srep35297<ref/>. | The Fv fragment of pembrolizumab (PemFv) can form a complex with the extracellular domain (ECD) of PD-1. Both PemFv and PD-1ECD contain interchain disulfide bonds. PemFv interacts predominantly in the major groove of PD-1, which is formed on one surface by the CC’FG antiparallel β−sheet and the BC, C’D, and FG loops. There are 15 direct hydrogen bonds between the residues, 15 water-mediated hydrogen bonds, 2 salt bridges, and many hydrophobic interactions. A very large solvent-accessible surface area of 1,137Å2 is buried on PD-1ECD due to the convoluted interaction. There are a total of 26 PD-1ECD residues involved in the interaction with PemFv, with residues in loop C’D (Pro84 to Gly90) and strand C’ (Gln75 to Lys 78) playing a major role. These key components of PD-1 mainly form interactions through salt bridges and hydrogen bonds with CRD-L3, CDR-H1, CDR-H2, CDR-H3 of pembrolizumab. It is beleived that the sugar chains of PD-1 have no phsyical contact with pembrolizumab due to the N-linked glycosylated residues (Asn49, Asn58, Asn74, and Asn116) being located away from the interaface <ref>DOI: 10.1038/srep35297<ref/>. | ||
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| + | == PD-L1/PD-1 Interaction == | ||
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| + | The complex formed when protein-derived ligand, PD-L1, interacts with the inhibitory receptor, PD-1, suppresses immune responses again autoantigens and helps in peripheral immune tolerance. However, when tumors overexpress PD-L1, the interaction with PD-1 inhibits T-lymphocyte proliferation, release of cytokines, and cytotoxicity, exhausting tumor-specific T-cells. There are a total of 12 PD-1ECD residues that are involved in forming the complex with the N-terminal half of PD-L1ECD (PD-L1ECD-N). Nine hydrogen bonds, 3 water-mediated hydrogen bonds, 2 salt bridges, and numerous hydrophobic interactions make up the PD-1ECD/PD-L1ECD-N interaction.The CC’FG sheet within both proteins is the main interaction point. A hydrophobic surface patch is formed when the PD-1ECD is in complex with PD-L1ECD-N. The PD-1ECD residues involved include Val64, Tyr68, Ile126, Leu128, Ala132 and Ile134. Numerous hydrophilic amino acids that encircle PD-L1ECD-N form salt bridges and hydrogen bonds with Asn66, Tyr68, Gln75, Thr76, Asp77, Lys78, Ala132 and Glu136 of PD-1ECD <ref>DOI: 10.1038/srep35297<ref/>. | ||
== Mechanism == | == Mechanism == | ||
Revision as of 18:52, 11 November 2016
Pembrolizumab as a Programmed Cell Death-1 Antagonist
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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>
