ArticleThe Journal of biological chemistry2014
Conformational response to ligand binding in phosphomannomutase2: insights into inborn glycosylation disorder.
Article in The Journal of biological chemistry, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 26 papers, 1 of them a synthesis that pooled it.
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Who cites it
26 citing papers in PubMed, 1 synthesis or guideline pooled it, 41 citations in OpenAlex.
- Systematic Review: Drug Repositioning for Congenital Disorders of Glycosylation (CDG).International journal of molecular sciences · 2022Pooled it
- Lipo-Glc-1,6-PIUBMB life · 2026Article
- Plasma membrane calcium ATPases and cerebellar pathology: what's the role in the ataxia?Biology direct · 2025Review
- Article
- Genotype/Phenotype Relationship: Lessons From 137 Patients With PMM2-CDG.Human mutation · 2024Observational
- Patient-Derived Cellular Models for Polytarget Precision Medicine in Pantothenate Kinase-Associated Neurodegeneration.Pharmaceuticals (Basel, Switzerland) · 2023Review
- Congenital disorders of glycosylation: narration of a story through its patents.Orphanet journal of rare diseases · 2023Review
- Genotype-Phenotype Correlations in PMM2-CDG.Genes · 2021Article
- Identification of GOLPH3 Partners inCells · 2021Article
- Non-functional alternative splicing caused by a Latino pathogenic variant in a case of PMM2-CDG.Molecular genetics and metabolism reports · 2021Article
- Crosstalk among Calcium ATPases: PMCA, SERCA and SPCA in Mental Diseases.International journal of molecular sciences · 2021Review
- Fatal outcome after heart surgery in PMM2-CDG due to a rare homozygous gene variant with double effects.Molecular genetics and metabolism reports · 2020Article
- Precision Medicine in Rare Diseases.Diseases (Basel, Switzerland) · 2020Review
- Second-Generation Pharmacological Chaperones: Beyond Inhibitors.Molecules (Basel, Switzerland) · 2020Review
- Hyperinsulinaemic Hypoglycaemia and Polycystic Kidney Disease - A Rare Case ConcerningEuropean endocrinology · 2020Article
- Pharmacological Chaperones: A Therapeutic Approach for Diseases Caused by Destabilizing Missense Mutations.International journal of molecular sciences · 2020Review
- Unsuccessful intravenous D-mannose treatment in PMM2-CDG.Orphanet journal of rare diseases · 2019Article
- β-Glucose-1,6-Bisphosphate Stabilizes Pathological Phophomannomutase2 Mutants In Vitro and Represents a Lead Compound to Develop Pharmacological Chaperones for the Most Common Disorder of Glycosylation, PMM2-CDG.International journal of molecular sciences · 2019Article
- Precision medicine in pantothenate kinase-associated neurodegeneration.Neural regeneration research · 2019Article
- The Analysis of Variants in the General Population Reveals ThatInternational journal of molecular sciences · 2018Article
Corrections and comments
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Authors and funding
6 authors at 4 institutions in 2 countries.
Funding
Abstract
The most common glycosylation disorder is caused by mutations in the gene encoding phosphomannomutase2, producing a disease still without a cure. Phosphomannomutase2, a homodimer in which each chain is composed of two domains, requires a bisphosphate sugar (either mannose or glucose) as activator, opening a possible drug design path for therapeutic purposes. The crystal structure of human phosphomannomutase2, however, lacks bound substrate and a key active site loop. To speed up drug discovery, we present here the first structural model of a bisphosphate substrate bound to human phosphomannomutase2. Taking advantage of recent developments in all-atom simulation techniques in combination with limited and site-directed proteolysis, we demonstrated that α-glucose 1,6-bisphosphate can adopt two low energy orientations as required for catalysis. Upon ligand binding, the two domains come close, making the protein more compact, in analogy to the enzyme in the crystals from Leishmania mexicana. Moreover, proteolysis was also carried out on two common mutants, R141H and F119L. It was an unexpected finding that the mutant most frequently found in patients, R141H, although inactive, does bind α-glucose 1,6-bisphosphate and changes conformation.
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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.