Proteopedia - User contributions [en]

Keytruda

2016-12-06T02:53:49Z

Lauren Riley:

==Pembrolizumab antibody against programmed cell death-1 receptor==
<StructureSection load='5dk3' size='350' side='right' caption='Full-Length Crystal Structure of Pembrolizumab (PDB code [[5dk3]])'>
== 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 at Asp297</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>.

== 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 [http://www.nature.com/articles/srep35297/figures/2 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. 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 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===
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-terminus 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 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-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 ==

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" />.

</StructureSection>

== References ==
<references/>

Keytruda

2016-12-06T02:43:33Z

Lauren Riley:

==Pembrolizumab antibody against programmed cell death-1 receptor==
<StructureSection load='5dk3' size='350' side='right' caption='Full-Length Crystal Structure of Pembrolizumab (PDB code [[5dk3]])'>
== 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 at Asp297</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>.

== Mechanism ==
[http://www.nature.com/articles/srep35297/figures/2 A schematic diagram of polar interactions]
===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. 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 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===
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-terminus 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 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-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 ==

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" />.

</StructureSection>

== References ==
<references/>

Sandbox454

2016-12-05T19:18:42Z

Lauren Riley:

==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>.

== 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>.
===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. 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 complementary determining region (CDR)-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 [http://www.nature.com/articles/srep35297/figures/1 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" />.<scene name='74/745945/Chain_b_amino_acids/1'>ChainB</scene>
== 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" />.

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/>

Sandbox454

2016-12-05T18:54:28Z

Lauren Riley:

==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>.

== 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>.
===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. 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 complementary determining region (CDR)-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 [http://www.nature.com/articles/srep35297/figures/1 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 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/>

Sandbox454

2016-11-11T19:15:56Z

Lauren Riley:

<Structure load='5GGS' size='340' frame='true' align='right' caption='PD-1 in complex with pembrolizumab Fab' scene='Insert optional scene name here' />== Pembrolizumab ==
<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.
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 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 glycosylated 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 and facing the solvent. 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 can be conquered by introducing a serine-to-proline mutation at amino acid 228, which prevents Fab-arm exchange and stabilizes the molecule <ref>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 it’s flat conformation when bound to PD-L1 <ref>DOI: 10.1038/srep35297<ref/>.

== 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/>.

== PD-L1/PD-1 Interaction ==

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 ==

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/>.

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.

</StructureSection>
== References ==
<references/>

Sandbox454

2016-11-11T19:14:53Z

Lauren Riley:

<Structure load='5GGS' size='350' frame='true' align='right' caption='PD-1 in complex with pembrolizumab Fab' scene='Insert optional scene name here' />== Pembrolizumab ==
<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.
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 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 glycosylated 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 and facing the solvent. 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 can be conquered by introducing a serine-to-proline mutation at amino acid 228, which prevents Fab-arm exchange and stabilizes the molecule <ref>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 it’s flat conformation when bound to PD-L1 <ref>DOI: 10.1038/srep35297<ref/>.

== 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/>.

== PD-L1/PD-1 Interaction ==

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 ==

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/>.

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.

</StructureSection>
== References ==
<references/>

Sandbox454

2016-11-11T18:58:18Z

Lauren Riley:

== Pembrolizumab as a Programmed Cell Death-1 Antagonist ==
<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.
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 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 glycosylated 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 and facing the solvent. 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 can be conquered by introducing a serine-to-proline mutation at amino acid 228, which prevents Fab-arm exchange and stabilizes the molecule <ref>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 it’s flat conformation when bound to PD-L1 <ref>DOI: 10.1038/srep35297<ref/>.

== PemFab/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/>.

== PD-L1/PD-1 Interaction ==

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 ==

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.
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.

</StructureSection>
== References ==
<references/>

File:Pdb5ggs.ent.gz

2016-11-11T18:56:19Z

Lauren Riley: