6umt

From Proteopedia

(Difference between revisions)

Revision as of 13:23, 18 December 2019

High-affinity human PD-1 PD-L2 complex

Structural highlights

6umt is a 2 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:
Gene:	PDCD1, PD1 (HUMAN), PDCD1LG2, B7DC, CD273, PDCD1L2, PDL2 (HUMAN)
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] [PD1L2_HUMAN] Involved in the costimulatory signal, essential for T-cell proliferation and IFNG production in a PDCD1-independent manner. Interaction with PDCD1 inhibits T-cell proliferation by blocking cell cycle progression and cytokine production (By similarity).

Publication Abstract from PubMed

Immune checkpoint blockade of programmed death-1 (PD-1) by monoclonal antibody drugs has delivered breakthroughs in the treatment of cancer. Nonetheless, small-molecule PD-1 inhibitors could lead to increases in treatment efficacy, safety, and global access. While the ligand-binding surface of apo-PD-1 is relatively flat, it harbors a striking pocket in the murine PD-1/PD-L2 structure. An analogous pocket in human PD-1 may serve as a small-molecule drug target, but the structure of the human complex is unknown. Because the CC' and FG loops in murine PD-1 adopt new conformations upon binding PD-L2, we hypothesized that mutations in these two loops could be coupled to pocket formation and alter PD-1's affinity for PD-L2. Here, we conducted deep mutational scanning in these loops and used yeast surface display to select for enhanced PD-L2 binding. A PD-1 variant with three substitutions binds PD-L2 with an affinity two orders of magnitude higher than that of the wild-type protein, permitting crystallization of the complex. We determined the X-ray crystal structures of the human triple-mutant PD-1/PD-L2 complex and the apo triple-mutant PD-1 variant at 2.0 A and 1.2 A resolution, respectively. Binding of PD-L2 is accompanied by formation of a prominent pocket in human PD-1, as well as substantial conformational changes in the CC' and FG loops. The structure of the apo triple-mutant PD-1 shows that the CC' loop adopts the ligand-bound conformation, providing support for allostery between the loop and pocket. This human PD-1/PD-L2 structure provide critical insights for the design and discovery of small-molecule PD-1 inhibitors.

A high-affinity human PD-1/PD-L2 complex informs avenues for small-molecule immune checkpoint drug discovery.,Tang S, Kim PS Proc Natl Acad Sci U S A. 2019 Nov 14. pii: 1916916116. doi:, 10.1073/pnas.1916916116. PMID:31727844^[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
↑ Tang S, Kim PS. A high-affinity human PD-1/PD-L2 complex informs avenues for small-molecule immune checkpoint drug discovery. Proc Natl Acad Sci U S A. 2019 Nov 14. pii: 1916916116. doi:, 10.1073/pnas.1916916116. PMID:31727844 doi:http://dx.doi.org/10.1073/pnas.1916916116

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

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/6umt"

@@ Line 3: / Line 3: @@
 <StructureSection load='6umt' size='340' side='right'caption='[[6umt]], [[Resolution|resolution]] 1.99&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[6umt]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6UMT OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6UMT FirstGlance]. <br>
+<table><tr><td colspan='2'>[[6umt]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6UMT OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6UMT FirstGlance]. <br>
 </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene></td></tr>
+<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">PDCD1, PD1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN]), PDCD1LG2, B7DC, CD273, PDCD1L2, PDL2 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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=6umt FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6umt OCA], [http://pdbe.org/6umt PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6umt RCSB], [http://www.ebi.ac.uk/pdbsum/6umt PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6umt ProSAT]</span></td></tr>
 </table>
@@ Line 24: / Line 25: @@
 __TOC__
 </StructureSection>
+[[Category: Human]]
 [[Category: Large Structures]]
 [[Category: Kim, P S]]

6umt

From Proteopedia

Revision as of 13:23, 18 December 2019

High-affinity human PD-1 PD-L2 complex

Structural highlights

Disease

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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