Evidence map›Paper›PMID 27618663›Full record

ArticleStructure (London, England : 1993)2016

Structure and Dynamics of PD-L1 and an Ultra-High-Affinity PD-1 Receptor Mutant.

Roberta Pascolutti, Xianqiang Sun, Joseph Kao, Roy L Maute, Aaron M Ring, Gregory R Bowman, Andrew C Kruse

Abstract read
In one paragraph

Article in Structure (London, England : 1993), 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 50 papers, 1 of them a synthesis that pooled it.

0numbers the graph read from it
0cells of the map it votes in
50citing papers in PubMed, 1 pooled it
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

50 citing papers in PubMed, 1 synthesis or guideline pooled it.

  1. Pooled it
  2. Article
  3. Article
  4. Article
  5. Article
  6. Review
  7. Article
  8. Review
  9. Article
  10. Article
  11. Article
  12. VSTM2A reverses immunosuppression in colorectal cancer by antagonizing the PD-L1/PD-1 interaction.Molecular therapy : the journal of the American Society of Gene Therapy · 2024
    Article
  13. Article
  14. Article
  15. Review
  16. Review
  17. In silico evolution of autoinhibitory domains for a PD-L1 antagonist using deep learning models.Proceedings of the National Academy of Sciences of the United States of America · 2023
    Article
  18. Article
  19. Article
  20. Article
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

7 authors.

Roberta PascoluttiDepartment of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
Xianqiang SunDepartment of Biochemistry & Molecular Biophysics, Washington University School of Medicine, St. Louis, MO 63110, USA.
Joseph KaoAb Initio Biotherapeutics, Inc., South San Francisco, CA 94080, USA.
Roy L MauteAb Initio Biotherapeutics, Inc., South San Francisco, CA 94080, USA.
Aaron M RingDepartment of Immunobiology, Yale School of Medicine, New Haven, CT 06519, USA.
Gregory R BowmanDepartment of Biochemistry & Molecular Biophysics, Washington University School of Medicine, St. Louis, MO 63110, USA.
Andrew C KruseDepartment of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA. Electronic address: andrew_kruse@hms.harvard.edu.

Funding

Molecular mechanisms of adiponectin signaling and PAQR functionDP5OD021345 · OD · HARVARD MEDICAL SCHOOL · PI KRUSE, ANDREW · 2015 to 2019
$2.1M
NIH HHS DP5 OD021345
6 · The paper itself

Abstract

The immune checkpoint receptor PD-1 and its ligand, PD-L1, have emerged as key regulators of anti-tumor immunity in humans. Recently, we reported an ultra-high-affinity PD-1 mutant, termed high-affinity consensus (HAC) PD-1, which shows superior therapeutic efficacy in mice compared with antibodies. However, the molecular details underlying the action of this agent remain incompletely understood, and a molecular view of PD-1/PD-L1 interactions in general is only beginning to emerge. Here, we report the structure of HAC PD-1 in complex with PD-L1, showing that it binds PD-L1 using a unique set of polar interactions. Biophysical studies and long-timescale molecular dynamics experiments reveal the mechanisms by which ten point mutations confer a 35,000-fold enhancement in binding affinity, and offer atomic-scale views of the role of conformational dynamics in PD-1/PD-L1 interactions. Finally, we show that the HAC PD-1 exhibits pH-dependent affinity, with pseudo-irreversible binding in a low pH setting akin to the tumor microenvironment.

Indexed as

Point MutationB7-H1 AntigenBinding SitesCrystallography, X-RayHumansHydrogen-Ion ConcentrationModels, MolecularMolecular Dynamics SimulationProgrammed Cell Death 1 ReceptorProtein BindingProtein Structure, SecondaryB7-H1 AntigenCD274 protein, humanPDCD1 protein, humanProgrammed Cell Death 1 Receptor

Identifiers

PMID27618663
PMCPMC5052120

What OpenQuestion holds

Textmetadata
LicenceTDM
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.