PDBsum entry 5n2d

Cell cycle

PDB id: 5n2d

Contents

Protein chains

125 a.a.

Ligands

8J8 ×2

Waters ×171

PDB id:

5n2d

Name:

Cell cycle

Title:

Structure of pd-l1/small-molecule inhibitor complex

Structure:

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

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: cd274, b7h1, pdcd1l1, pdcd1lg1, pdl1. Expressed in: escherichia coli. Expression_system_taxid: 562

Resolution:

2.35Å R-factor: 0.213 R-free: 0.267

Authors:

K.Guzik,K.M.Zak,P.Grudnik,G.Dubin,T.A.Holak

Key ref:

K.Guzik et al. (2017). Small-Molecule Inhibitors of the Programmed Cell Death-1/Programmed Death-Ligand 1 (PD-1/PD-L1) Interaction via Transiently Induced Protein States and Dimerization of PD-L1. J Med Chem, 60, 5857-5867. PubMed id: 28613862 DOI: 10.1021/acs.jmedchem.7b00293

Date:

07-Feb-17 Release date: 28-Jun-17

Protein chains

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

Seq: 290 a.a.

Struc: 125 a.a.*

* PDB and UniProt seqs differ at 8 residue positions (black crosses)

DOI no: 10.1021/acs.jmedchem.7b00293

J Med Chem 60:5857-5867 (2017)

PubMed id: 28613862

Small-Molecule Inhibitors of the Programmed Cell Death-1/Programmed Death-Ligand 1 (PD-1/PD-L1) Interaction via Transiently Induced Protein States and Dimerization of PD-L1.

K.Guzik, K.M.Zak, P.Grudnik, K.Magiera, B.Musielak, R.Törner, L.Skalniak, A.Dömling, G.Dubin, T.A.Holak.

ABSTRACT

Blockade of the PD-1/PD-L1 immune checkpoint pathway with monoclonal antibodies has provided significant advances in cancer treatment. The antibody-based immunotherapies carry a number of disadvantages such as the high cost of the antibodies, their limited half-life, and immunogenicity. Development of small-molecule PD-1/PD-L1 inhibitors that could overcome these drawbacks is slow because of the incomplete structural information for this pathway. The first chemical PD-1/PD-L1 inhibitors have been recently disclosed by Bristol-Myers Squibb. Here we present NMR and X-ray characterization for the two classes of these inhibitors. The X-ray structures of the PD-L1/inhibitor complexes reveal one inhibitor molecule located at the center of the PD-L1 homodimer, filling a deep hydrophobic channel-like pocket between two PD-L1 molecules. Derivatives of (2-methyl-3-biphenylyl)methanol exhibit the structures capped on one side of the channel, whereas the compounds based on [3-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-methylphenyl]methanol induce an enlarged interaction interface that results in the open "face-back" tunnel through the PD-L1 dimer.