5j89: Difference between revisions

Latest revision as of 10:53, 6 September 2023

Structure of human Programmed cell death 1 ligand 1 (PD-L1) with low molecular mass inhibitor

Structural highlights

5j89 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 2.2Å
Ligands:	6GX, EDO
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

Targeting the PD-1/PD-L1 immunologic checkpoint with monoclonal antibodies has provided unprecedented results in cancer treatment in the recent years. Development of chemical inhibitors for this pathway lags the antibody development because of insufficient structural information. The first nonpeptidic chemical inhibitors that target the PD-1/PD-L1 interaction have only been recently disclosed by Bristol-Myers Squibb. Here, we show that these small-molecule compounds bind directly to PD-L1 and that they potently block PD-1 binding. Structural studies reveal a dimeric protein complex with a single small molecule which stabilizes the dimer thus occluding the PD-1 interaction surface of PD-L1s. The small-molecule interaction "hot spots" on PD-L1 surfaces suggest approaches for the PD-1/PD-L1 antagonist drug discovery.

Structural basis for small molecule targeting of the programmed death ligand 1 (PD-L1).,Zak KM, Grudnik P, Guzik K, Zieba BJ, Musielak B, Domling A, Dubin G, Holak TA Oncotarget. 2016 Apr 13. doi: 10.18632/oncotarget.8730. PMID:27083005^[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
↑ Zak KM, Grudnik P, Guzik K, Zieba BJ, Musielak B, Domling A, Dubin G, Holak TA. Structural basis for small molecule targeting of the programmed death ligand 1 (PD-L1). Oncotarget. 2016 Apr 13. doi: 10.18632/oncotarget.8730. PMID:27083005 doi:https://dx.doi.org/10.18632/oncotarget.8730

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OCA

[1] 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

[2] 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

[3] Zak KM, Grudnik P, Guzik K, Zieba BJ, Musielak B, Domling A, Dubin G, Holak TA. Structural basis for small molecule targeting of the programmed death ligand 1 (PD-L1). Oncotarget. 2016 Apr 13. doi: 10.18632/oncotarget.8730. PMID:27083005 doi:https://dx.doi.org/10.18632/oncotarget.8730

[1]

[2]

[3]

@@ Line 3: / Line 3: @@
 <StructureSection load='5j89' size='340' side='right'caption='[[5j89]], [[Resolution|resolution]] 2.20&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[5j89]] is a 4 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=5J89 OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=5J89 FirstGlance]. <br>
+<table><tr><td colspan='2'>[[5j89]] 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=5J89 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5J89 FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=6GX:N-{2-[({2-METHOXY-6-[(2-METHYL[1,1-BIPHENYL]-3-YL)METHOXY]PYRIDIN-3-YL}METHYL)AMINO]ETHYL}ACETAMIDE'>6GX</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</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]] 2.2&#8491;</td></tr>
-<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">CD274, B7H1, PDCD1L1, PDCD1LG1, PDL1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=6GX:N-{2-[({2-METHOXY-6-[(2-METHYL[1,1-BIPHENYL]-3-YL)METHOXY]PYRIDIN-3-YL}METHYL)AMINO]ETHYL}ACETAMIDE'>6GX</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene></td></tr>
-<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=5j89 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5j89 OCA], [http://pdbe.org/5j89 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5j89 RCSB], [http://www.ebi.ac.uk/pdbsum/5j89 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5j89 ProSAT]</span></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=5j89 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5j89 OCA], [https://pdbe.org/5j89 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5j89 RCSB], [https://www.ebi.ac.uk/pdbsum/5j89 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5j89 ProSAT]</span></td></tr>
 </table>
 == Function ==
-[[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/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 ==
@@ Line 23: / Line 23: @@
 __TOC__
 </StructureSection>
-[[Category: Human]]
+[[Category: Homo sapiens]]
 [[Category: Large Structures]]
-[[Category: Doemling, P]]
+[[Category: Doemling P]]
-[[Category: Dubin, G]]
+[[Category: Dubin G]]
-[[Category: Grudnik, P]]
+[[Category: Grudnik P]]
-[[Category: Guzik, K]]
+[[Category: Guzik K]]
-[[Category: Holak, T A]]
+[[Category: Holak TA]]
-[[Category: Musielak, B]]
+[[Category: Musielak B]]
-[[Category: Zak, K M]]
+[[Category: Zak KM]]
-[[Category: Zieba, B J]]
+[[Category: Zieba BJ]]
-[[Category: Cell cycle]]
-[[Category: Immune system]]
-[[Category: Pd-l1]]
-[[Category: Programmed cell death 1 ligand 1]]

5j89: Difference between revisions

Latest revision as of 10:53, 6 September 2023

Structure of human Programmed cell death 1 ligand 1 (PD-L1) with low molecular mass inhibitor

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

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