PDBsum entry 6vqn

Cell cycle

PDB id: 6vqn

Contents

Protein chains

121 a.a.

Ligands

R81 ×2

Waters ×139

PDB id:

6vqn

Name:

Cell cycle

Title:

Co-crystal structure of human pd-l1 complexed with compound a

Structure:

Programmed cell death 1 ligand 1. Chain: a, b, c. Synonym: hpd-l1,b7 homolog 1,b7-h1. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: cd274, b7h1, pdcd1l1, pdcd1lg1, pdl1. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008.

Resolution:

2.49Å R-factor: 0.179 R-free: 0.228

Authors:

A.White,D.Lakshminarasimhan,C.Leo,R.K.Suto

Key ref:

J.J.Park et al. (2021). Checkpoint inhibition through small molecule-induced internalization of programmed death-ligand 1. Nat Commun, 12, 1222. PubMed id: 33619272 DOI: 10.1038/s41467-021-21410-1

Date:

05-Feb-20 Release date: 20-Jan-21

Protein chains

Q9NZQ7  (PD1L1_HUMAN) -  Programmed cell death 1 ligand 1 from Homo sapiens

Seq: 290 a.a.

Struc: 121 a.a.*

* PDB and UniProt seqs differ at 4 residue positions (black crosses)

DOI no: 10.1038/s41467-021-21410-1

Nat Commun 12:1222 (2021)

PubMed id: 33619272

Checkpoint inhibition through small molecule-induced internalization of programmed death-ligand 1.

J.J.Park, E.P.Thi, V.H.Carpio, Y.Bi, A.G.Cole, B.D.Dorsey, K.Fan, T.Harasym, C.L.Iott, S.Kadhim, J.H.Kim, A.C.H.Lee, D.Nguyen, B.S.Paratala, R.Qiu, A.White, D.Lakshminarasimhan, C.Leo, R.K.Suto, R.Rijnbrand, S.Tang, M.J.Sofia, C.B.Moore.

ABSTRACT

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.