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5ius

From Proteopedia

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Crystal structure of human PD-L1 in complex with high affinity PD-1 mutant

Structural highlights

5ius is a 4 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.889Å
Ligands:
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

PDCD1_HUMAN Systemic lupus erythematosus;Multiple sclerosis. Systemic lupus erythematosus 2 (SLEB2) [MIM:605218: A chronic, relapsing, inflammatory, and often febrile multisystemic disorder of connective tissue, characterized principally by involvement of the skin, joints, kidneys and serosal membranes. It is of unknown etiology, but is thought to represent a failure of the regulatory mechanisms of the autoimmune system. The disease is marked by a wide range of system dysfunctions, an elevated erythrocyte sedimentation rate, and the formation of LE cells in the blood or bone marrow. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.^[1]

Function

PDCD1_HUMAN Inhibitory cell surface receptor involved in the regulation of T-cell function during immunity and tolerance. Upon ligand binding, inhibits T-cell effector functions in an antigen-specific manner. Possible cell death inducer, in association with other factors.^[2]

Publication Abstract from PubMed

The immune checkpoint receptor PD-1 and its ligand, PD-L1, have emerged as key regulators of anti-tumor immunity in humans. Recently, we reported an ultra-high-affinity PD-1 mutant, termed high-affinity consensus (HAC) PD-1, which shows superior therapeutic efficacy in mice compared with antibodies. However, the molecular details underlying the action of this agent remain incompletely understood, and a molecular view of PD-1/PD-L1 interactions in general is only beginning to emerge. Here, we report the structure of HAC PD-1 in complex with PD-L1, showing that it binds PD-L1 using a unique set of polar interactions. Biophysical studies and long-timescale molecular dynamics experiments reveal the mechanisms by which ten point mutations confer a 35,000-fold enhancement in binding affinity, and offer atomic-scale views of the role of conformational dynamics in PD-1/PD-L1 interactions. Finally, we show that the HAC PD-1 exhibits pH-dependent affinity, with pseudo-irreversible binding in a low pH setting akin to the tumor microenvironment.

Structure and Dynamics of PD-L1 and an Ultra-High-Affinity PD-1 Receptor Mutant.,Pascolutti R, Sun X, Kao J, Maute RL, Ring AM, Bowman GR, Kruse AC Structure. 2016 Sep 7. pii: S0969-2126(16)30229-5. doi:, 10.1016/j.str.2016.06.026. PMID:27618663^[3]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Prokunina L, Castillejo-Lopez C, Oberg F, Gunnarsson I, Berg L, Magnusson V, Brookes AJ, Tentler D, Kristjansdottir H, Grondal G, Bolstad AI, Svenungsson E, Lundberg I, Sturfelt G, Jonssen A, Truedsson L, Lima G, Alcocer-Varela J, Jonsson R, Gyllensten UB, Harley JB, Alarcon-Segovia D, Steinsson K, Alarcon-Riquelme ME. A regulatory polymorphism in PDCD1 is associated with susceptibility to systemic lupus erythematosus in humans. Nat Genet. 2002 Dec;32(4):666-9. Epub 2002 Oct 28. PMID:12402038 doi:10.1038/ng1020
↑ Fife BT, Pauken KE. The role of the PD-1 pathway in autoimmunity and peripheral tolerance. Ann N Y Acad Sci. 2011 Jan;1217:45-59. doi: 10.1111/j.1749-6632.2010.05919.x. PMID:21276005 doi:10.1111/j.1749-6632.2010.05919.x
↑ Pascolutti R, Sun X, Kao J, Maute RL, Ring AM, Bowman GR, Kruse AC. Structure and Dynamics of PD-L1 and an Ultra-High-Affinity PD-1 Receptor Mutant. Structure. 2016 Sep 7. pii: S0969-2126(16)30229-5. doi:, 10.1016/j.str.2016.06.026. PMID:27618663 doi:http://dx.doi.org/10.1016/j.str.2016.06.026

1 Structural highlights
2 Disease
3 Function
4 Publication Abstract from PubMed
5 See Also
6 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/5ius"

@@ Line 1: / Line 1: @@
 ==Crystal structure of human PD-L1 in complex with high affinity PD-1 mutant==
-<StructureSection load='5ius' size='340' side='right' caption='[[5ius]], [[Resolution|resolution]] 2.89&Aring;' scene=''>
+<StructureSection load='5ius' size='340' side='right'caption='[[5ius]], [[Resolution|resolution]] 2.89&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[5ius]] is a 4 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5IUS OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5IUS FirstGlance]. <br>
+<table><tr><td colspan='2'>[[5ius]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5IUS OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5IUS FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene></td></tr>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.889&#8491;</td></tr>
-<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5ius FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5ius OCA], [http://pdbe.org/5ius PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5ius RCSB], [http://www.ebi.ac.uk/pdbsum/5ius PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5ius ProSAT]</span></td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene></td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=5ius FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5ius OCA], [https://pdbe.org/5ius PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5ius RCSB], [https://www.ebi.ac.uk/pdbsum/5ius PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5ius ProSAT]</span></td></tr>
 </table>
 == Disease ==
-[[http://www.uniprot.org/uniprot/PDCD1_HUMAN PDCD1_HUMAN]] Systemic lupus erythematosus;Multiple sclerosis. Systemic lupus erythematosus 2 (SLEB2) [MIM:[http://omim.org/entry/605218 605218]]: A chronic, relapsing, inflammatory, and often febrile multisystemic disorder of connective tissue, characterized principally by involvement of the skin, joints, kidneys and serosal membranes. It is of unknown etiology, but is thought to represent a failure of the regulatory mechanisms of the autoimmune system. The disease is marked by a wide range of system dysfunctions, an elevated erythrocyte sedimentation rate, and the formation of LE cells in the blood or bone marrow. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.<ref>PMID:12402038</ref>
+[https://www.uniprot.org/uniprot/PDCD1_HUMAN PDCD1_HUMAN] Systemic lupus erythematosus;Multiple sclerosis. Systemic lupus erythematosus 2 (SLEB2) [MIM:[https://omim.org/entry/605218 605218]: A chronic, relapsing, inflammatory, and often febrile multisystemic disorder of connective tissue, characterized principally by involvement of the skin, joints, kidneys and serosal membranes. It is of unknown etiology, but is thought to represent a failure of the regulatory mechanisms of the autoimmune system. The disease is marked by a wide range of system dysfunctions, an elevated erythrocyte sedimentation rate, and the formation of LE cells in the blood or bone marrow. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.<ref>PMID:12402038</ref>
 == Function ==
-[[http://www.uniprot.org/uniprot/PDCD1_HUMAN PDCD1_HUMAN]] Inhibitory cell surface receptor involved in the regulation of T-cell function during immunity and tolerance. Upon ligand binding, inhibits T-cell effector functions in an antigen-specific manner. Possible cell death inducer, in association with other factors.<ref>PMID:21276005</ref>  [[http://www.uniprot.org/uniprot/PD1L1_HUMAN PD1L1_HUMAN]] Involved in the costimulatory signal, essential for T-cell proliferation and production of IL10 and IFNG, in an IL2-dependent and a PDCD1-independent manner. Interaction with PDCD1 inhibits T-cell proliferation and cytokine production.<ref>PMID:10581077</ref> <ref>PMID:11015443</ref>
+[https://www.uniprot.org/uniprot/PDCD1_HUMAN PDCD1_HUMAN] Inhibitory cell surface receptor involved in the regulation of T-cell function during immunity and tolerance. Upon ligand binding, inhibits T-cell effector functions in an antigen-specific manner. Possible cell death inducer, in association with other factors.<ref>PMID:21276005</ref>
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
@@ Line 20: / Line 21: @@
 </div>
 <div class="pdbe-citations 5ius" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[Cell death protein 3D structures|Cell death protein 3D structures]]
 == References ==
 <references/>
 __TOC__
 </StructureSection>
-[[Category: Bowman, G R]]
+[[Category: Homo sapiens]]
-[[Category: Kao, J]]
+[[Category: Large Structures]]
-[[Category: Kruse, A C]]
+[[Category: Bowman GR]]
-[[Category: Maute, R]]
+[[Category: Kao J]]
-[[Category: Pascolutti, R]]
+[[Category: Kruse AC]]
-[[Category: Ring, A M]]
+[[Category: Maute R]]
-[[Category: Sun, X]]
+[[Category: Pascolutti R]]
-[[Category: Cancer]]
+[[Category: Ring AM]]
-[[Category: Immune checkpoint]]
+[[Category: Sun X]]
-[[Category: Immune system]]
-[[Category: Receptor]]
-[[Category: Tumor surveillance]]

5ius

From Proteopedia

Current revision

Crystal structure of human PD-L1 in complex with high affinity PD-1 mutant

Structural highlights

Disease

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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