Pembrolizumab/Keytruda - Revision history

Emily Bradshaw. at 14:48, 19 April 2019

Emily Bradshaw. — Fri, 19 Apr 2019 14:48:09 GMT

←Older revision		Revision as of 14:48, 19 April 2019
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	== References ==		== References ==
	<references/>		<references/>
		+	Melanie Kusakavitch was a contributing author.

Michal Harel at 15:47, 16 January 2017

Michal Harel — Mon, 16 Jan 2017 15:47:22 GMT

←Older revision		Revision as of 15:47, 16 January 2017
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	== Structure and Function ==		== Structure and Function ==

-	Pembrolizumab, trade name Keytruda, is an immunoglobulin G4 (IgG4)-kappa humanized monoclonal antibody against the programmed cell death-1 (PD-1) receptor. It contains an Fv fragment (PemFv) that is the variable region of the molecule where binding orccurs, as well as a Fab fragment (PemFab) that constitutes the entire molecule. Pembrolizumab is a very compact molecule with an asymmetrical Y-shape. The short compact hinge region inflicts constraints on the molecule that creates the abnormal crystallizable heavy chain/tail region (Fc domain) compared to other immunoglobulin G (IgG) proteins. The heavy chain is <scene name='74/745945/Glycosylation/1'>glycosylated</scene> at both CH<sub>2</sub> domains on each chain and one of them is distinctively rotated 120° compared to other similar structures, making the glycan chain more solvent accessible. IgG4s have a unique function where they form dynamic bispecific antibodies by exchanging half-molecules (one heavy chain/light chain pair) among themselves, called Fab-arm exchange. This makes the molecule particularly unstable and unpredictable as a treatment, but is conquered by introducing the serine-to-proline mutation at <scene name='74/745945/Pro228/1'>amino acid 228</scene>, which prevents Fab-arm exchange and stabilizes the molecule <ref name="log">DOI:10.1080/17425255.2016.1216976</ref>.	+	'''Pembrolizumab''', trade name '''Keytruda''', is an immunoglobulin G4 (IgG4)-kappa humanized monoclonal antibody against the programmed cell death-1 (PD-1) receptor. It contains an Fv fragment (PemFv) that is the variable region of the molecule where binding orccurs, as well as a Fab fragment (PemFab) that constitutes the entire molecule. Pembrolizumab is a very compact molecule with an asymmetrical Y-shape. The short compact hinge region inflicts constraints on the molecule that creates the abnormal crystallizable heavy chain/tail region (Fc domain) compared to other immunoglobulin G (IgG) proteins. The heavy chain is <scene name='74/745945/Glycosylation/1'>glycosylated</scene> at both CH<sub>2</sub> domains on each chain and one of them is distinctively rotated 120° compared to other similar structures, making the glycan chain more solvent accessible. IgG4s have a unique function where they form dynamic bispecific antibodies by exchanging half-molecules (one heavy chain/light chain pair) among themselves, called Fab-arm exchange. This makes the molecule particularly unstable and unpredictable as a treatment, but is conquered by introducing the serine-to-proline mutation at <scene name='74/745945/Pro228/1'>amino acid 228</scene>, which prevents Fab-arm exchange and stabilizes the molecule <ref name="log">DOI:10.1080/17425255.2016.1216976</ref>.

	== Mechanism ==		== Mechanism ==

Emily Bradshaw. at 23:15, 5 December 2016

Emily Bradshaw. — Mon, 05 Dec 2016 23:15:49 GMT

←Older revision		Revision as of 23:15, 5 December 2016
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	== Structure and Function ==		== Structure and Function ==

-	Pembrolizumab, or Keytruda, is an immunoglobulin G4 (IgG4)-kappa humanized monoclonal antibody against the programmed cell death-1 (PD-1) receptor. It contains an Fv fragment (PemFv) that is the variable region of the molecule where binding orccurs, as well as a Fab fragment (PemFab) that constitutes the entire molecule. Pembrolizumab is a very compact molecule with an asymmetrical Y-shape. The short compact hinge region inflicts constraints on the molecule that creates the abnormal crystallizable heavy chain/tail region (Fc domain) compared to other immunoglobulin G (IgG) proteins. The heavy chain is <scene name='74/745945/Glycosylation/1'>glycosylated</scene> at both CH<sub>2</sub> domains on each chain and one of them is distinctively rotated 120° compared to other similar structures, making the glycan chain more solvent accessible. IgG4s have a unique function where they form dynamic bispecific antibodies by exchanging half-molecules (one heavy chain/light chain pair) among themselves, called Fab-arm exchange. This makes the molecule particularly unstable and unpredictable as a treatment, but is conquered by introducing the serine-to-proline mutation at <scene name='74/745945/Pro228/1'>amino acid 228</scene>, which prevents Fab-arm exchange and stabilizes the molecule <ref name="log">DOI:10.1080/17425255.2016.1216976</ref>.	+	Pembrolizumab, trade name Keytruda, is an immunoglobulin G4 (IgG4)-kappa humanized monoclonal antibody against the programmed cell death-1 (PD-1) receptor. It contains an Fv fragment (PemFv) that is the variable region of the molecule where binding orccurs, as well as a Fab fragment (PemFab) that constitutes the entire molecule. Pembrolizumab is a very compact molecule with an asymmetrical Y-shape. The short compact hinge region inflicts constraints on the molecule that creates the abnormal crystallizable heavy chain/tail region (Fc domain) compared to other immunoglobulin G (IgG) proteins. The heavy chain is <scene name='74/745945/Glycosylation/1'>glycosylated</scene> at both CH<sub>2</sub> domains on each chain and one of them is distinctively rotated 120° compared to other similar structures, making the glycan chain more solvent accessible. IgG4s have a unique function where they form dynamic bispecific antibodies by exchanging half-molecules (one heavy chain/light chain pair) among themselves, called Fab-arm exchange. This makes the molecule particularly unstable and unpredictable as a treatment, but is conquered by introducing the serine-to-proline mutation at <scene name='74/745945/Pro228/1'>amino acid 228</scene>, which prevents Fab-arm exchange and stabilizes the molecule <ref name="log">DOI:10.1080/17425255.2016.1216976</ref>.

	== Mechanism ==		== Mechanism ==

Emily Bradshaw. at 23:14, 5 December 2016

Emily Bradshaw. — Mon, 05 Dec 2016 23:14:28 GMT

←Older revision		Revision as of 23:14, 5 December 2016
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-	==Pembrolizumab~~/Keytruda~~==	+	==Pembrolizumab Antibody Against PD-1 Receptor==
	<StructureSection load='5dk3' size='350' side='right' caption='Full-Length Crystal Structure of Pembrolizumab (PDB code [[5dk3]])'>		<StructureSection load='5dk3' size='350' side='right' caption='Full-Length Crystal Structure of Pembrolizumab (PDB code [[5dk3]])'>
	== Structure and Function ==		== Structure and Function ==

Emily Bradshaw. at 23:09, 5 December 2016

Emily Bradshaw. — Mon, 05 Dec 2016 23:09:20 GMT

←Older revision		Revision as of 23:09, 5 December 2016
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	T-cells are a major component of the immune response in the human body. They have the ability to recognize cancer-related antigens as non-self and eliminate those cells <ref>doi 10.2147/DDDT.S78036</ref>. PD-L1 and PD-L2 are ligands expressed by some tumors and inhibit T-cell function when bound to PD-1, which is located on the surface of antigen-specific T-cells <ref>doi 10.1007/s40265-016-0543-x</ref>. When PD-L1 is ligated to PD-1 an adaptive immune response occurs, and this allows cancer cells to bypass immune surveillance and grow uncontrollably. Pembrolizumab is an FDA-approved treatment that works as a PD-1 pathway inhibitor to fight numerous forms of cancer, such as metastatic melanoma and non-small cell lung cancer. As an inhibitor, Pembrolizumab targets the cell death of PD-1 and blocks the immune checkpoint pathway. Pembrolizumab has a very high affinity to PD-1, allowing it to block the interaction between PD-1 with PD-L1 and PD-L2 very efficiently. It antagonizes the interaction between PD-1 and its known ligands, and re-activates anti-tumor immunity <ref name="log" />. 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. One downside of Pembrolizumab is that it may cause inflammatory side effects <ref name="horita" />.		T-cells are a major component of the immune response in the human body. They have the ability to recognize cancer-related antigens as non-self and eliminate those cells <ref>doi 10.2147/DDDT.S78036</ref>. PD-L1 and PD-L2 are ligands expressed by some tumors and inhibit T-cell function when bound to PD-1, which is located on the surface of antigen-specific T-cells <ref>doi 10.1007/s40265-016-0543-x</ref>. When PD-L1 is ligated to PD-1 an adaptive immune response occurs, and this allows cancer cells to bypass immune surveillance and grow uncontrollably. Pembrolizumab is an FDA-approved treatment that works as a PD-1 pathway inhibitor to fight numerous forms of cancer, such as metastatic melanoma and non-small cell lung cancer. As an inhibitor, Pembrolizumab targets the cell death of PD-1 and blocks the immune checkpoint pathway. Pembrolizumab has a very high affinity to PD-1, allowing it to block the interaction between PD-1 with PD-L1 and PD-L2 very efficiently. It antagonizes the interaction between PD-1 and its known ligands, and re-activates anti-tumor immunity <ref name="log" />. 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. One downside of Pembrolizumab is that it may cause inflammatory side effects <ref name="horita" />.
-
-	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.

	</StructureSection>		</StructureSection>

Emily Bradshaw. at 23:08, 5 December 2016

Emily Bradshaw. — Mon, 05 Dec 2016 23:08:53 GMT

←Older revision		Revision as of 23:08, 5 December 2016
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	==Pembrolizumab/Keytruda==		==Pembrolizumab/Keytruda==
	<StructureSection load='5dk3' size='350' side='right' caption='Full-Length Crystal Structure of Pembrolizumab (PDB code [[5dk3]])'>		<StructureSection load='5dk3' size='350' side='right' caption='Full-Length Crystal Structure of Pembrolizumab (PDB code [[5dk3]])'>
-	Click above on '''edit this page''' to modify. Be careful with the < and > signs.
-	You may include any references to papers as in: the use of JSmol in Proteopedia <ref>DOI 10.1002/ijch.201300024</ref> or to the article describing Jmol <ref>PMID:21638687</ref> to the rescue.
-
	== Structure and Function ==		== Structure and Function ==

Emily Bradshaw. at 23:06, 5 December 2016

Emily Bradshaw. — Mon, 05 Dec 2016 23:06:47 GMT

←Older revision		Revision as of 23:06, 5 December 2016
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	== Structure and Function ==		== Structure and Function ==

-	Pembrolizumab, or Keytruda, is an immunoglobulin G4 (IgG4)-kappa humanized monoclonal antibody against the programmed cell death-1 (PD-1) receptor. It contains an Fv fragment (PemFv) ~~and a Fab fragment (PemFab). The Fv fragment~~ is the variable region of the molecule where binding ~~occurs whereas the~~ Fab fragment constitutes the entire molecule. Pembrolizumab is a very compact molecule with an asymmetrical Y-shape. The short compact hinge region inflicts constraints on the molecule that creates the abnormal crystallizable tail region (Fc domain) compared to other immunoglobulin G (IgG) proteins. The ~~Fc domain~~ is <scene name='74/745945/Glycosylation/1'>glycosylated</scene> at both CH<sub>2</sub> domains on each chain and one of them is distinctively rotated 120° compared to other similar structures, making the glycan chain more solvent accessible. IgG4s have a unique function where they form dynamic bispecific antibodies by exchanging half-molecules (one heavy chain/light chain pair) among themselves, called Fab-arm exchange. This makes the molecule particularly unstable and unpredictable as a treatment, but is conquered by introducing the serine-to-proline mutation at <scene name='74/745945/Pro228/1'>amino acid 228</scene>, which prevents Fab-arm exchange and stabilizes the molecule <ref name="log">DOI:10.1080/17425255.2016.1216976</ref>.	+	Pembrolizumab, or Keytruda, is an immunoglobulin G4 (IgG4)-kappa humanized monoclonal antibody against the programmed cell death-1 (PD-1) receptor. It contains an Fv fragment (PemFv) that is the variable region of the molecule where binding orccurs, as well as a Fab fragment (PemFab) that constitutes the entire molecule. Pembrolizumab is a very compact molecule with an asymmetrical Y-shape. The short compact hinge region inflicts constraints on the molecule that creates the abnormal crystallizable heavy chain/tail region (Fc domain) compared to other immunoglobulin G (IgG) proteins. The heavy chain is <scene name='74/745945/Glycosylation/1'>glycosylated</scene> at both CH<sub>2</sub> domains on each chain and one of them is distinctively rotated 120° compared to other similar structures, making the glycan chain more solvent accessible. IgG4s have a unique function where they form dynamic bispecific antibodies by exchanging half-molecules (one heavy chain/light chain pair) among themselves, called Fab-arm exchange. This makes the molecule particularly unstable and unpredictable as a treatment, but is conquered by introducing the serine-to-proline mutation at <scene name='74/745945/Pro228/1'>amino acid 228</scene>, which prevents Fab-arm exchange and stabilizes the molecule <ref name="log">DOI:10.1080/17425255.2016.1216976</ref>.

	== Mechanism ==		== Mechanism ==
Line 12:		Line 12:
	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~~. A very large solvent-accessible surface area of 1,137Å<sup>2</sup> is buried on PD-1<sub>ECD</sub> due to the convoluted interaction~~. 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 ~~CRD-L3~~, ~~CDR-H1~~, ~~CDR-H2~~, ~~CDR-H3~~ of Pembrolizumab. 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" />.	+	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, Tys101, 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-terminal half of PD-1<sub>ECD</sub> (PD-1<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-1<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 include Val64, Tyr68, Ile126, Leu128, Ala132 and Ile134. Numerous ~~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-terminal half of PD-1<sub>ECD</sub> (PD-1<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-1<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 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" />.
-		+
	== Disease in Humans - Cancer ==		== Disease in Humans - Cancer ==

-	T-cells are a major component of the immune response in the human body. They have the ability to recognize cancer-related antigens as non-self and eliminate those cells <ref>doi 10.2147/DDDT.S78036</ref>. PD-L1 and PD-L2 are ligands expressed by some tumors and inhibit T-cell function when bound to PD-1, which is located on the surface of antigen-specific T-cells <ref>doi 10.1007/s40265-016-0543-x</ref>. When PD-L1 is ligated to PD-1 an adaptive immune response occurs, and this allows cancer cells to bypass immune surveillance and grow uncontrollably. Pembrolizumab is an FDA-approved treatment that works as a PD-1 pathway inhibitor to fight numerous forms of cancer, such as metastatic melanoma and non-small cell lung cancer. As an inhibitor, Pembrolizumab targets the cell death of PD-1 and blocks the immune checkpoint pathway. Pembrolizumab has a very high affinity to PD-1, allowing it to block the interaction between PD-1 with PD-L1 and PD-L2 very efficiently. It antagonizes the interaction between PD-1 and its known ligands, and re-activates anti-tumor immunity <ref name="log" />. 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. One downside of Pembrolizumab is that it may cause inflammatory side effects <ref name="horita" />.	+	T-cells are a major component of the immune response in the human body. They have the ability to recognize cancer-related antigens as non-self and eliminate those cells <ref>doi 10.2147/DDDT.S78036</ref>. PD-L1 and PD-L2 are ligands expressed by some tumors and inhibit T-cell function when bound to PD-1, which is located on the surface of antigen-specific T-cells <ref>doi 10.1007/s40265-016-0543-x</ref>. When PD-L1 is ligated to PD-1 an adaptive immune response occurs, and this allows cancer cells to bypass immune surveillance and grow uncontrollably. Pembrolizumab is an FDA-approved treatment that works as a PD-1 pathway inhibitor to fight numerous forms of cancer, such as metastatic melanoma and non-small cell lung cancer. As an inhibitor, Pembrolizumab targets the cell death of PD-1 and blocks the immune checkpoint pathway. Pembrolizumab has a very high affinity to PD-1, allowing it to block the interaction between PD-1 with PD-L1 and PD-L2 very efficiently. It antagonizes the interaction between PD-1 and its known ligands, and re-activates anti-tumor immunity <ref name="log" />. 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. One downside of Pembrolizumab is that it may cause inflammatory side effects <ref name="horita" />.

	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.		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.

Emily Bradshaw. at 00:50, 2 December 2016

Emily Bradshaw. — Fri, 02 Dec 2016 00:50:21 GMT

←Older revision		Revision as of 00:50, 2 December 2016
Line 1:		Line 1:
	==Pembrolizumab/Keytruda==		==Pembrolizumab/Keytruda==
-	<StructureSection load='5dk3' size='350' side='right' caption='Full-Length Crystal Structure of Pembrolizumab (PDB code: [[~~5DK3~~]]) '>	+	<StructureSection load='5dk3' size='350' side='right' caption='Full-Length Crystal Structure of Pembrolizumab (PDB code [[5dk3]])'>
	Click above on '''edit this page''' to modify. Be careful with the < and > signs.		Click above on '''edit this page''' to modify. Be careful with the < and > signs.
	You may include any references to papers as in: the use of JSmol in Proteopedia <ref>DOI 10.1002/ijch.201300024</ref> or to the article describing Jmol <ref>PMID:21638687</ref> to the rescue.		You may include any references to papers as in: the use of JSmol in Proteopedia <ref>DOI 10.1002/ijch.201300024</ref> or to the article describing Jmol <ref>PMID:21638687</ref> to the rescue.
Line 8:		Line 8:
	Pembrolizumab, or Keytruda, is an immunoglobulin G4 (IgG4)-kappa humanized monoclonal antibody against the programmed cell death-1 (PD-1) receptor. It contains an Fv fragment (PemFv) and a Fab fragment (PemFab). The Fv fragment is the variable region of the molecule where binding occurs whereas the Fab fragment constitutes the entire molecule. Pembrolizumab is a very compact molecule with an asymmetrical Y-shape. The short compact hinge region inflicts constraints on the molecule that creates the abnormal crystallizable tail region (Fc domain) compared to other immunoglobulin G (IgG) proteins. The Fc domain is <scene name='74/745945/Glycosylation/1'>glycosylated</scene> at both CH<sub>2</sub> domains on each chain and one of them is distinctively rotated 120° compared to other similar structures, making the glycan chain more solvent accessible. IgG4s have a unique function where they form dynamic bispecific antibodies by exchanging half-molecules (one heavy chain/light chain pair) among themselves, called Fab-arm exchange. This makes the molecule particularly unstable and unpredictable as a treatment, but is conquered by introducing the serine-to-proline mutation at <scene name='74/745945/Pro228/1'>amino acid 228</scene>, which prevents Fab-arm exchange and stabilizes the molecule <ref name="log">DOI:10.1080/17425255.2016.1216976</ref>.		Pembrolizumab, or Keytruda, is an immunoglobulin G4 (IgG4)-kappa humanized monoclonal antibody against the programmed cell death-1 (PD-1) receptor. It contains an Fv fragment (PemFv) and a Fab fragment (PemFab). The Fv fragment is the variable region of the molecule where binding occurs whereas the Fab fragment constitutes the entire molecule. Pembrolizumab is a very compact molecule with an asymmetrical Y-shape. The short compact hinge region inflicts constraints on the molecule that creates the abnormal crystallizable tail region (Fc domain) compared to other immunoglobulin G (IgG) proteins. The Fc domain is <scene name='74/745945/Glycosylation/1'>glycosylated</scene> at both CH<sub>2</sub> domains on each chain and one of them is distinctively rotated 120° compared to other similar structures, making the glycan chain more solvent accessible. IgG4s have a unique function where they form dynamic bispecific antibodies by exchanging half-molecules (one heavy chain/light chain pair) among themselves, called Fab-arm exchange. This makes the molecule particularly unstable and unpredictable as a treatment, but is conquered by introducing the serine-to-proline mutation at <scene name='74/745945/Pro228/1'>amino acid 228</scene>, which prevents Fab-arm exchange and stabilizes the molecule <ref name="log">DOI:10.1080/17425255.2016.1216976</ref>.

-	== Pembrolizumab/PD-1 Interaction ==	+	== Mechanism ==
-		+	===Pembrolizumab/PD-1 Interaction===
	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. A very large solvent-accessible surface area of 1,137Å<sup>2</sup> is buried on PD-1<sub>ECD</sub> due to the convoluted interaction. 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 CRD-L3, CDR-H1, CDR-H2, CDR-H3 of Pembrolizumab. 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" />.		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. A very large solvent-accessible surface area of 1,137Å<sup>2</sup> is buried on PD-1<sub>ECD</sub> due to the convoluted interaction. 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 CRD-L3, CDR-H1, CDR-H2, CDR-H3 of Pembrolizumab. 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-terminal half of PD-1<sub>ECD</sub> (PD-1<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-1<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 include Val64, Tyr68, Ile126, Leu128, Ala132 and Ile134. Numerous 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-terminal half of PD-1<sub>ECD</sub> (PD-1<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-1<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 include Val64, Tyr68, Ile126, Leu128, Ala132 and Ile134. Numerous 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-~~1ECD~~ <ref name="horita" />.	+

	== Disease in Humans - Cancer ==		== Disease in Humans - Cancer ==

-	T-cells are a major component of the immune response in the human body. They have the ability to recognize cancer-related antigens as non-self and eliminate those cells <ref>doi 10.2147/DDDT.S78036</ref>. PD-L1 and PD-L2 are ligands expressed by some tumors and inhibit T-cell function when bound to PD-1, which is located on the surface of antigen-specific T-cells <ref>doi 10.1007/s40265-016-0543-x</ref>. When PD-L1 is ligated to PD-1 an adaptive immune response occurs, and this allows cancer cells to bypass ~~the~~ immune surveillance and grow uncontrollably. Pembrolizumab is an FDA-approved treatment that works as a PD-1 pathway inhibitor to fight numerous forms of cancer, such as metastatic melanoma and non-small cell lung cancer. As an inhibitor, Pembrolizumab targets the cell death of PD-1 and blocks the immune checkpoint pathway. Pembrolizumab has a very high affinity to PD-1, allowing it to block the interaction between PD-1 with PD-L1 and PD-L2 very efficiently. It antagonizes the interaction between PD-1 and its known ligands, and re-activates anti-tumor immunity <ref name="log" />. 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. One downside of Pembrolizumab is that it may cause inflammatory side effects <ref name="horita" />.	+	T-cells are a major component of the immune response in the human body. They have the ability to recognize cancer-related antigens as non-self and eliminate those cells <ref>doi 10.2147/DDDT.S78036</ref>. PD-L1 and PD-L2 are ligands expressed by some tumors and inhibit T-cell function when bound to PD-1, which is located on the surface of antigen-specific T-cells <ref>doi 10.1007/s40265-016-0543-x</ref>. When PD-L1 is ligated to PD-1 an adaptive immune response occurs, and this allows cancer cells to bypass immune surveillance and grow uncontrollably. Pembrolizumab is an FDA-approved treatment that works as a PD-1 pathway inhibitor to fight numerous forms of cancer, such as metastatic melanoma and non-small cell lung cancer. As an inhibitor, Pembrolizumab targets the cell death of PD-1 and blocks the immune checkpoint pathway. Pembrolizumab has a very high affinity to PD-1, allowing it to block the interaction between PD-1 with PD-L1 and PD-L2 very efficiently. It antagonizes the interaction between PD-1 and its known ligands, and re-activates anti-tumor immunity <ref name="log" />. 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. One downside of Pembrolizumab is that it may cause inflammatory side effects <ref name="horita" />.

	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.		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.

Emily Bradshaw.: New page: ==Pembrolizumab/Keytruda== Click above on '''edit this...

Emily Bradshaw. — Fri, 02 Dec 2016 00:18:30 GMT

New page: ==Pembrolizumab/Keytruda== <StructureSection load='5dk3' size='350' side='right' caption='Full-Length Crystal Structure of Pembrolizumab (PDB code: 5DK3) '> Click above on '''edit this...

New page

==Pembrolizumab/Keytruda==
<StructureSection load='5dk3' size='350' side='right' caption='Full-Length Crystal Structure of Pembrolizumab (PDB code: [[5DK3]]) '>
Click above on '''edit this page''' to modify. Be careful with the < and > signs.
You may include any references to papers as in: the use of JSmol in Proteopedia <ref>DOI 10.1002/ijch.201300024</ref> or to the article describing Jmol <ref>PMID:21638687</ref> to the rescue.

== Structure and Function ==

Pembrolizumab, or Keytruda, is an immunoglobulin G4 (IgG4)-kappa humanized monoclonal antibody against the programmed cell death-1 (PD-1) receptor. It contains an Fv fragment (PemFv) and a Fab fragment (PemFab). The Fv fragment is the variable region of the molecule where binding occurs whereas the Fab fragment constitutes the entire molecule. Pembrolizumab is a very compact molecule with an asymmetrical Y-shape. The short compact hinge region inflicts constraints on the molecule that creates the abnormal crystallizable tail region (Fc domain) compared to other immunoglobulin G (IgG) proteins. The Fc domain is <scene name='74/745945/Glycosylation/1'>glycosylated</scene> at both CH2 domains on each chain and one of them is distinctively rotated 120° compared to other similar structures, making the glycan chain more solvent accessible. IgG4s have a unique function where they form dynamic bispecific antibodies by exchanging half-molecules (one heavy chain/light chain pair) among themselves, called Fab-arm exchange. This makes the molecule particularly unstable and unpredictable as a treatment, but is conquered by introducing the serine-to-proline mutation at <scene name='74/745945/Pro228/1'>amino acid 228</scene>, which prevents Fab-arm exchange and stabilizes the molecule <ref name="log">DOI:10.1080/17425255.2016.1216976</ref>.

== Pembrolizumab/PD-1 Interaction ==

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 ==

The Fv fragment of Pembrolizumab 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 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 ==

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-1ECD residues that are involved in forming the complex with the N-terminal half of PD-1ECD (PD-1ECD-N). Nine hydrogen bonds, 3 water-mediated hydrogen bonds, 2 salt bridges, and numerous hydrophobic interactions make up the PD-1ECD/PD-1ECD-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 name="horita" />.

== Disease in Humans - Cancer ==

T-cells are a major component of the immune response in the human body. They have the ability to recognize cancer-related antigens as non-self and eliminate those cells <ref>doi 10.2147/DDDT.S78036</ref>. PD-L1 and PD-L2 are ligands expressed by some tumors and inhibit T-cell function when bound to PD-1, which is located on the surface of antigen-specific T-cells <ref>doi 10.1007/s40265-016-0543-x</ref>. When PD-L1 is ligated to PD-1 an adaptive immune response occurs, and this allows cancer cells to bypass the immune surveillance and grow uncontrollably. Pembrolizumab is an FDA-approved treatment that works as a PD-1 pathway inhibitor to fight numerous forms of cancer, such as metastatic melanoma and non-small cell lung cancer. As an inhibitor, Pembrolizumab targets the cell death of PD-1 and blocks the immune checkpoint pathway. Pembrolizumab has a very high affinity to PD-1, allowing it to block the interaction between PD-1 with PD-L1 and PD-L2 very efficiently. It antagonizes the interaction between PD-1 and its known ligands, and re-activates anti-tumor immunity <ref name="log" />. 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. One downside of Pembrolizumab is that it may cause inflammatory side effects <ref name="horita" />.

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.

</StructureSection>

== References ==
<references/>