6vqn | pdb_00006vqn

Co-crystal structure of human PD-L1 complexed with Compound A

Structural highlights

6vqn is a 3 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 2.49Å
Ligands:	R81
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

Programmed death-ligand 1 is a glycoprotein expressed on antigen presenting cells, hepatocytes, and tumors which upon interaction with programmed death-1, results in inhibition of antigen-specific T cell responses. Here, we report a mechanism of inhibiting programmed death-ligand 1 through small molecule-induced dimerization and internalization. This represents a mechanism of checkpoint inhibition, which differentiates from anti-programmed death-ligand 1 antibodies which function through molecular disruption of the programmed death 1 interaction. Testing of programmed death ligand 1 small molecule inhibition in a humanized mouse model of colorectal cancer results in a significant reduction in tumor size and promotes T cell proliferation. In addition, antigen-specific T and B cell responses from patients with chronic hepatitis B infection are significantly elevated upon programmed death ligand 1 small molecule inhibitor treatment. Taken together, these data identify a mechanism of small molecule-induced programmed death ligand 1 internalization with potential therapeutic implications in oncology and chronic viral infections.

Checkpoint inhibition through small molecule-induced internalization of programmed death-ligand 1.,Park JJ, Thi EP, Carpio VH, Bi Y, Cole AG, Dorsey BD, Fan K, Harasym T, Iott CL, Kadhim S, Kim JH, Lee ACH, Nguyen D, Paratala BS, Qiu R, White A, Lakshminarasimhan D, Leo C, Suto RK, Rijnbrand R, Tang S, Sofia MJ, Moore CB Nat Commun. 2021 Feb 22;12(1):1222. doi: 10.1038/s41467-021-21410-1. PMID:33619272^[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
↑ Park JJ, Thi EP, Carpio VH, Bi Y, Cole AG, Dorsey BD, Fan K, Harasym T, Iott CL, Kadhim S, Kim JH, Lee ACH, Nguyen D, Paratala BS, Qiu R, White A, Lakshminarasimhan D, Leo C, Suto RK, Rijnbrand R, Tang S, Sofia MJ, Moore CB. Checkpoint inhibition through small molecule-induced internalization of programmed death-ligand 1. Nat Commun. 2021 Feb 22;12(1):1222. doi: 10.1038/s41467-021-21410-1. PMID:33619272 doi:https://dx.doi.org/10.1038/s41467-021-21410-1

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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] Park JJ, Thi EP, Carpio VH, Bi Y, Cole AG, Dorsey BD, Fan K, Harasym T, Iott CL, Kadhim S, Kim JH, Lee ACH, Nguyen D, Paratala BS, Qiu R, White A, Lakshminarasimhan D, Leo C, Suto RK, Rijnbrand R, Tang S, Sofia MJ, Moore CB. Checkpoint inhibition through small molecule-induced internalization of programmed death-ligand 1. Nat Commun. 2021 Feb 22;12(1):1222. doi: 10.1038/s41467-021-21410-1. PMID:33619272 doi:https://dx.doi.org/10.1038/s41467-021-21410-1

[1]

[2]

[3]

6vqn | pdb_00006vqn

Co-crystal structure of human PD-L1 complexed with Compound A

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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