Keytruda: Difference between revisions
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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 the flat conformation when bound to PD-L1 <ref name="horita">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 the flat conformation when bound to PD-L1 <ref name="horita">DOI:10.1038/srep35297</ref>. | ||
===PemFv/PD-1 Interaction=== | ===PemFv/PD-1 Interaction=== | ||
The Fv fragment of Pembrolizumab can form a complex with the extracellular domain (ECD) of PD-1. Both PemFv and PD-1<sub>ECD</sub> 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. There are a total of 26 PD-1<sub>ECD</sub> 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 complementary determining regions, the variable domains, of Pembrolizumab. <scene name='74/745945/Chain_b_amino_acids/1'>Thr30, Tyr33, Ser54, | The Fv fragment of Pembrolizumab can form a complex with the extracellular domain (ECD) of PD-1. Both PemFv and PD-1<sub>ECD</sub> 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. There are a total of 26 PD-1<sub>ECD</sub> 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 complementary determining regions, the variable domains, of Pembrolizumab. <scene name='74/745945/Chain_b_amino_acids/1'>Thr30, Tyr33, Ser54, Tyr101, Arg102</scene> on Chain B of Pembrolizumab form bonds with Asp77, Gln75, Lys78, Thr76, Tyr68, and Asn66 of PD-1. It is believed that the sugar chains of PD-1 have no physical contact with Pembrolizumab due to the N-linked glycosylated residues (Asn49, Asn58, Asn74, and Asn116) being located away from the interface <ref name="horita" />. | ||
===PD-L1/PD-1 Interaction=== | ===PD-L1/PD-1 Interaction=== | ||
The complex formed when protein-derived ligand, PD-L1, interacts with the inhibitory receptor, PD-1, suppresses immune responses against autoantigens and helps in peripheral immune tolerance. However, when tumors over express 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-1<sub>ECD</sub> residues that are involved in forming the complex with the N-terminus of PD-L1<sub>ECD</sub> (PD-L1<sub>ECD-N</sub>). Nine hydrogen bonds, 3 water-mediated hydrogen bonds, 2 salt bridges, and numerous hydrophobic interactions make up the PD-1<sub>ECD</sub>/PD-L1<sub>ECD-N</sub> interaction. The CC’FG sheet within both proteins is the main interaction point. A hydrophobic surface patch is formed when the PD-1<sub>ECD</sub> is in complex with PD-L1<sub>ECD-N</sub>. The PD-1<sub>ECD</sub> residues involved in this include Val64, Tyr68, Ile126, Leu128, Ala132 and Ile134. Numerous [http://www.nature.com/articles/srep35297/figures/1 Hydrophilic amino acids] that encircle PD-L1<sub>ECD-N</sub> form salt bridges and hydrogen bonds with Asn66, Tyr68, Gln75, Thr76, Asp77, Lys78, Ala132 and Glu136 of PD-1<sub>ECD</sub> <ref name="horita" />. | The complex formed when protein-derived ligand, PD-L1, interacts with the inhibitory receptor, PD-1, suppresses immune responses against autoantigens and helps in peripheral immune tolerance. However, when tumors over express 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-1<sub>ECD</sub> residues that are involved in forming the complex with the N-terminus of PD-L1<sub>ECD</sub> (PD-L1<sub>ECD-N</sub>). Nine hydrogen bonds, 3 water-mediated hydrogen bonds, 2 salt bridges, and numerous hydrophobic interactions make up the PD-1<sub>ECD</sub>/PD-L1<sub>ECD-N</sub> interaction. The CC’FG sheet within both proteins is the main interaction point. A hydrophobic surface patch is formed when the PD-1<sub>ECD</sub> is in complex with PD-L1<sub>ECD-N</sub>. The PD-1<sub>ECD</sub> residues involved in this include Val64, Tyr68, Ile126, Leu128, Ala132 and Ile134. Numerous [http://www.nature.com/articles/srep35297/figures/1 Hydrophilic amino acids] that encircle PD-L1<sub>ECD-N</sub> form salt bridges and hydrogen bonds with Asn66, Tyr68, Gln75, Thr76, Asp77, Lys78, Ala132 and Glu136 of PD-1<sub>ECD</sub> <ref name="horita" />. | ||