6r3k: Difference between revisions

Latest revision as of 12:14, 24 January 2024

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

Structural highlights

6r3k is a 4 chain structure with sequence from Homo sapiens. This structure supersedes the now removed PDB entry 5nix. 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:	EDO, JQT
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

We describe a new class of potent PD-L1/PD-1 inhibitors based on a terphenyl scaffold that is derived from the rigidified biphenyl-inspired structure. Using in silico docking, we designed and then experimentally demonstrated the effectiveness of the terphenyl-based scaffolds in inhibiting PD-1/PD-L1 complex formation using various biophysical and biochemical techniques. We also present a high-resolution structure of the complex of PD-L1 with one of our most potent inhibitors to identify key PD-L1/inhibitor interactions at the molecular level. In addition, we show the efficacy of our most potent inhibitors in activating the antitumor response using primary human immune cells from healthy donors.

Terphenyl-Based Small-Molecule Inhibitors of Programmed Cell Death-1/Programmed Death-Ligand 1 Protein-Protein Interaction.,Muszak D, Surmiak E, Plewka J, Magiera-Mularz K, Kocik-Krol J, Musielak B, Sala D, Kitel R, Stec M, Weglarczyk K, Siedlar M, Domling A, Skalniak L, Holak TA J Med Chem. 2021 Jul 27. doi: 10.1021/acs.jmedchem.1c00957. PMID:34313116^[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
↑ Muszak D, Surmiak E, Plewka J, Magiera-Mularz K, Kocik-Krol J, Musielak B, Sala D, Kitel R, Stec M, Weglarczyk K, Siedlar M, Domling A, Skalniak L, Holak TA. Terphenyl-Based Small-Molecule Inhibitors of Programmed Cell Death-1/Programmed Death-Ligand 1 Protein-Protein Interaction. J Med Chem. 2021 Jul 27. doi: 10.1021/acs.jmedchem.1c00957. PMID:34313116 doi:https://dx.doi.org/10.1021/acs.jmedchem.1c00957

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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] Muszak D, Surmiak E, Plewka J, Magiera-Mularz K, Kocik-Krol J, Musielak B, Sala D, Kitel R, Stec M, Weglarczyk K, Siedlar M, Domling A, Skalniak L, Holak TA. Terphenyl-Based Small-Molecule Inhibitors of Programmed Cell Death-1/Programmed Death-Ligand 1 Protein-Protein Interaction. J Med Chem. 2021 Jul 27. doi: 10.1021/acs.jmedchem.1c00957. PMID:34313116 doi:https://dx.doi.org/10.1021/acs.jmedchem.1c00957

[1]

[2]

[3]

@@ Line 1: / Line 1: @@
-'''Unreleased structure'''
-The entry 6r3k is ON HOLD
+==Structure of human Programmed cell death 1 ligand 1 (PD-L1) with low molecular mass inhibitor==
+<StructureSection load='6r3k' size='340' side='right'caption='[[6r3k]], [[Resolution|resolution]] 2.20&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[6r3k]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. This structure supersedes the now removed PDB entry [http://oca.weizmann.ac.il/oca-bin/send-pdb?obs=1&id=5nix 5nix]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6R3K OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6R3K 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]] 2.2&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=JQT:(2~{S},4~{R})-1-[[5-chloranyl-2-[(3-cyanophenyl)methoxy]-4-[[3-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-methyl-phenyl]methoxy]phenyl]methyl]-4-oxidanyl-pyrrolidine-2-carboxylic+acid'>JQT</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=6r3k FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6r3k OCA], [https://pdbe.org/6r3k PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6r3k RCSB], [https://www.ebi.ac.uk/pdbsum/6r3k PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6r3k 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 ==
+We describe a new class of potent PD-L1/PD-1 inhibitors based on a terphenyl scaffold that is derived from the rigidified biphenyl-inspired structure. Using in silico docking, we designed and then experimentally demonstrated the effectiveness of the terphenyl-based scaffolds in inhibiting PD-1/PD-L1 complex formation using various biophysical and biochemical techniques. We also present a high-resolution structure of the complex of PD-L1 with one of our most potent inhibitors to identify key PD-L1/inhibitor interactions at the molecular level. In addition, we show the efficacy of our most potent inhibitors in activating the antitumor response using primary human immune cells from healthy donors.
-Authors: Zak, K.M., Grudnik, P., Skalniak, L., Dubin, G., Holak, T.A.
+Terphenyl-Based Small-Molecule Inhibitors of Programmed Cell Death-1/Programmed Death-Ligand 1 Protein-Protein Interaction.,Muszak D, Surmiak E, Plewka J, Magiera-Mularz K, Kocik-Krol J, Musielak B, Sala D, Kitel R, Stec M, Weglarczyk K, Siedlar M, Domling A, Skalniak L, Holak TA J Med Chem. 2021 Jul 27. doi: 10.1021/acs.jmedchem.1c00957. PMID:34313116<ref>PMID:34313116</ref>
-Description: Structure of human Programmed cell death 1 ligand 1 (PD-L1) with low molecular mass inhibitor
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-[[Category: Unreleased Structures]]
+</div>
-[[Category: Grudnik, P]]
+<div class="pdbe-citations 6r3k" style="background-color:#fffaf0;"></div>
-[[Category: Zak, K.M]]
+== References ==
-[[Category: Holak, T.A]]
+<references/>
-[[Category: Dubin, G]]
+__TOC__
-[[Category: Skalniak, L]]
+</StructureSection>
+[[Category: Homo sapiens]]
+[[Category: Large Structures]]
+[[Category: Dubin G]]
+[[Category: Grudnik P]]
+[[Category: Holak TA]]
+[[Category: Skalniak L]]
+[[Category: Zak KM]]

6r3k: Difference between revisions

Latest revision as of 12:14, 24 January 2024

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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