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7dy7

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Discovery of Novel Small-molecule Inhibitors of PD-1/PD-L1 Axis that Promotes PD-L1 Internalization and Degradation

Structural highlights

7dy7 is a 2 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 2.42Å
Ligands:
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

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.^[1] ^[2]

Publication Abstract from PubMed

Several monoclonal antibodies targeting the programmed cell death-1/programmed cell death-ligand 1 (PD-1/PD-L1) pathway have been used successfully in anticancer immunotherapy. Inherent limitations of antibody-based therapies remain, however, and alternative small-molecule inhibitors that can block the PD-1/PD-L1 axis are urgent needed. Herein, we report the discovery of compound 17 as a bifunctional inhibitor of PD-1/PD-L1 interactions. 17 inhibits PD-1/PD-L1 interactions and promotes dimerization, internalization, and degradation of PD-L1. 17 promotes cell-surface PD-L1 internalized into the cytosol and induces the degradation of PD-L1 in tumor cells through a lysosome-dependent pathway. Furthermore, 17 suppresses tumor growth in vivo by activating antitumor immunity. These results demonstrate that 17 targets the PD-1/PD-L1 axis and induces PD-L1 degradation.

Discovery of Small-Molecule Inhibitors of the PD-1/PD-L1 Axis That Promote PD-L1 Internalization and Degradation.,Wang T, Cai S, Cheng Y, Zhang W, Wang M, Sun H, Guo B, Li Z, Xiao Y, Jiang S J Med Chem. 2022 Mar 10;65(5):3879-3893. doi: 10.1021/acs.jmedchem.1c01682. Epub , 2022 Feb 21. PMID:35188766^[3]

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

References

↑ Dong H, Zhu G, Tamada K, Chen L. B7-H1, a third member of the B7 family, co-stimulates T-cell proliferation and interleukin-10 secretion. Nat Med. 1999 Dec;5(12):1365-9. PMID:10581077 doi:10.1038/70932
↑ Freeman GJ, Long AJ, Iwai Y, Bourque K, Chernova T, Nishimura H, Fitz LJ, Malenkovich N, Okazaki T, Byrne MC, Horton HF, Fouser L, Carter L, Ling V, Bowman MR, Carreno BM, Collins M, Wood CR, Honjo T. Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. J Exp Med. 2000 Oct 2;192(7):1027-34. PMID:11015443
↑ Wang T, Cai S, Cheng Y, Zhang W, Wang M, Sun H, Guo B, Li Z, Xiao Y, Jiang S. Discovery of Small-Molecule Inhibitors of the PD-1/PD-L1 Axis That Promote PD-L1 Internalization and Degradation. J Med Chem. 2022 Mar 10;65(5):3879-3893. doi: 10.1021/acs.jmedchem.1c01682. Epub , 2022 Feb 21. PMID:35188766 doi:http://dx.doi.org/10.1021/acs.jmedchem.1c01682

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

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/7dy7"

@@ Line 1: / Line 1: @@
-'''Unreleased structure'''
-The entry 7dy7 is ON HOLD
+==Discovery of Novel Small-molecule Inhibitors of PD-1/PD-L1 Axis that Promotes PD-L1 Internalization and Degradation==
+<StructureSection load='7dy7' size='340' side='right'caption='[[7dy7]], [[Resolution|resolution]] 2.42&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[7dy7]] is a 2 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=7DY7 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7DY7 FirstGlance]. <br>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.42&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=HOU:2-[[3-[[5-(2-methyl-3-phenyl-phenyl)-1,3,4-oxadiazol-2-yl]amino]phenyl]methylamino]ethanol'>HOU</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=7dy7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7dy7 OCA], [https://pdbe.org/7dy7 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7dy7 RCSB], [https://www.ebi.ac.uk/pdbsum/7dy7 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7dy7 ProSAT]</span></td></tr>
+</table>
+== Function ==
+[https://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>
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+Several monoclonal antibodies targeting the programmed cell death-1/programmed cell death-ligand 1 (PD-1/PD-L1) pathway have been used successfully in anticancer immunotherapy. Inherent limitations of antibody-based therapies remain, however, and alternative small-molecule inhibitors that can block the PD-1/PD-L1 axis are urgent needed. Herein, we report the discovery of compound 17 as a bifunctional inhibitor of PD-1/PD-L1 interactions. 17 inhibits PD-1/PD-L1 interactions and promotes dimerization, internalization, and degradation of PD-L1. 17 promotes cell-surface PD-L1 internalized into the cytosol and induces the degradation of PD-L1 in tumor cells through a lysosome-dependent pathway. Furthermore, 17 suppresses tumor growth in vivo by activating antitumor immunity. These results demonstrate that 17 targets the PD-1/PD-L1 axis and induces PD-L1 degradation.
-Authors:
+Discovery of Small-Molecule Inhibitors of the PD-1/PD-L1 Axis That Promote PD-L1 Internalization and Degradation.,Wang T, Cai S, Cheng Y, Zhang W, Wang M, Sun H, Guo B, Li Z, Xiao Y, Jiang S J Med Chem. 2022 Mar 10;65(5):3879-3893. doi: 10.1021/acs.jmedchem.1c01682. Epub , 2022 Feb 21. PMID:35188766<ref>PMID:35188766</ref>
-Description:
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-[[Category: Unreleased Structures]]
+</div>
+<div class="pdbe-citations 7dy7" style="background-color:#fffaf0;"></div>
+== References ==
+<references/>
+__TOC__
+</StructureSection>
+[[Category: Homo sapiens]]
+[[Category: Large Structures]]
+[[Category: Cheng Y]]
+[[Category: Jiang S]]
+[[Category: Lu ML]]
+[[Category: Wang TY]]
+[[Category: Xiao YB]]

7dy7

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Current revision

Discovery of Novel Small-molecule Inhibitors of PD-1/PD-L1 Axis that Promotes PD-L1 Internalization and Degradation

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

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