Evidence map›Paper›PMID 31703801›Full record

ArticleBiophysical journal2019

Machine Learning for Prioritization of Thermostabilizing Mutations for G-Protein Coupled Receptors.

Sanychen Muk, Soumadwip Ghosh, Srisairam Achuthan, Xiaomin Chen, XiaoJie Yao, Manbir Sandhu, Matthew C Griffor, Kimberly F Fennell, Ye Che, Veerabahu Shanmugasundaram and 3 more

Abstract read
In one paragraph

Article in Biophysical journal, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.

0numbers the graph read from it
0cells of the map it votes in
11citing papers in PubMed
–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

11 citing papers in PubMed.

  1. Article
  2. Discovery of Therapeutic Antibodies Targeting Complex Multi-Spanning Membrane Proteins.BioDrugs : clinical immunotherapeutics, biopharmaceuticals and gene therapy · 2024
    Review
  3. Article
  4. Article
  5. Article
  6. Article
  7. Article
  8. Article
  9. An online GPCR structure analysis platform.Nature structural & molecular biology · 2021
    Article
  10. Article
  11. Review
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

13 authors.

Sanychen MukDepartment of Computational and Quantitative Medicine, Beckman Research Institute of the City of Hope, Duarte, California.
Soumadwip GhoshDepartment of Computational and Quantitative Medicine, Beckman Research Institute of the City of Hope, Duarte, California.
Srisairam AchuthanDepartment of Computational and Quantitative Medicine, Beckman Research Institute of the City of Hope, Duarte, California.
Xiaomin ChenDiscovery Sciences, Pfizer, Groton, Connecticut.
XiaoJie YaoDiscovery Sciences, Pfizer, Groton, Connecticut.
Manbir SandhuDepartment of Computational and Quantitative Medicine, Beckman Research Institute of the City of Hope, Duarte, California.
Matthew C GrifforDiscovery Sciences, Pfizer, Groton, Connecticut.
Kimberly F FennellDiscovery Sciences, Pfizer, Groton, Connecticut.
Ye CheDiscovery Sciences, Pfizer, Groton, Connecticut.
Veerabahu ShanmugasundaramDiscovery Sciences, Pfizer, Groton, Connecticut.
Xiayang QiuDiscovery Sciences, Pfizer, Groton, Connecticut.
Christopher G TateMRC Laboratory of Molecular Biology, Cambridge, United Kingdom.
Nagarajan VaidehiDepartment of Computational and Quantitative Medicine, Beckman Research Institute of the City of Hope, Duarte, California. Electronic address: nvaidehi@coh.org.

Funding

Structural dynamics underlying GPCR-G protein selectivityR01GM117923 · NIGMS · BECKMAN RESEARCH INSTITUTE/CITY OF HOPE · PI VAIDEHI, NAGARAJAN · 2017 to 2024
$3.8M
Computationally Guided Design of Thermostable mutants of Neurotensin receptor1R01GM097261 · NIGMS · BECKMAN RESEARCH INSTITUTE/CITY OF HOPE · PI VAIDEHI, NAGARAJAN · 2011 to 2018
$2.3M
Medical Research Council MC_U105197215NIGMS NIH HHS R01 GM097261NIGMS NIH HHS R01 GM117923
6 · The paper itself

Abstract

Although the three-dimensional structures of G-protein coupled receptors (GPCRs), the largest superfamily of drug targets, have enabled structure-based drug design, there are no structures available for 87% of GPCRs. This is due to the stiff challenge in purifying the inherently flexible GPCRs. Identifying thermostabilized mutant GPCRs via systematic alanine scanning mutations has been a successful strategy in stabilizing GPCRs, but it remains a daunting task for each GPCR. We developed a computational method that combines sequence-, structure-, and dynamics-based molecular properties of GPCRs that recapitulate GPCR stability, with four different machine learning methods to predict thermostable mutations ahead of experiments. This method has been trained on thermostability data for 1231 mutants, the largest publicly available data set. A blind prediction for thermostable mutations of the complement factor C5a receptor 1 retrieved 36% of the thermostable mutants in the top 50 prioritized mutants compared to 3% in the first 50 attempts using systematic alanine scanning.

Indexed as

Molecular Dynamics SimulationMutationAlanineAmino Acid SubstitutionHEK293 CellsHumansMachine LearningProtein DomainsProtein StabilityReceptor, Anaphylatoxin C5aSequence AnalysisAlanineReceptor, Anaphylatoxin C5a

Identifiers

PMID31703801
PMCPMC6895739

What OpenQuestion holds

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Registered trials

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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.