ArticleStructure (London, England : 1993)2022
Triangulating variation in the population to define mechanisms for precision management of genetic disease.
Article in Structure (London, England : 1993), 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 7 papers.
What it found
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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.
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Who cites it
7 citing papers in PubMed, 8 citations in OpenAlex.
- Spatial covariance reveals isothiocyanate natural products adjust redox stress to restore function in alpha-1-antitrypsin deficiency.Cell reports. Medicine · 2025Article
- COPII cage assembly factor Sec13 integrates information flow regulating endomembrane function in response to human variation.Scientific reports · 2024Article
- Tracing genetic diversity captures the molecular basis of misfolding disease.Nature communications · 2024Article
- Understanding the host-pathogen evolutionary balance through Gaussian process modeling of SARS-CoV-2.Patterns (New York, N.Y.) · 2023Article
- Rescue of Rare CFTR Trafficking Mutants Highlights a Structural Location-Dependent Pattern for Correction.International journal of molecular sciences · 2023Article
- Capturing the conversion of the pathogenic alpha-1-antitrypsin fold by ATF6 enhanced proteostasis.Cell chemical biology · 2023Article
- Spatial covariance analysis reveals the residue-by-residue thermodynamic contribution of variation to the CFTR fold.Communications biology · 2022Article
Corrections and comments
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Authors and funding
3 authors at 2 institutions in 1 country.
Funding
Abstract
To understand mechanistically how the protein fold is shaped by therapeutics to inform precision management of disease, we developed variation-capture (VarC) mapping. VarC triangulates sparse sequence variation information found in the population using Gaussian process regression (GPR)-based machine learning to define the combined pairwise-residue interactions contributing to dynamic protein function in the individual in response to therapeutics. Using VarC mapping, we now reveal the pairwise-residue covariant relationships across the entire protein fold of cystic fibrosis (CF) transmembrane conductance regulator (CFTR) to define the molecular mechanisms of clinically approved CF chemical modulators. We discover an energetically destabilized covariant core containing a di-acidic YKDAD endoplasmic reticulum (ER) exit code that is only weakly corrected by current therapeutics. Our results illustrate that VarC provides a generalizable tool to triangulate information from genetic variation in the population to mechanistically discover therapeutic strategies that guide precision management of the individual.
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What OpenQuestion holds
Registered trials
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.