Evidence map›Paper›PMID 33116203›Full record

ArticleScientific reports2020

Conformational gating, dynamics and allostery in human monoacylglycerol lipase.

Sergiy Tyukhtenko, Xiaoyu Ma, Girija Rajarshi, Ioannis Karageorgos, Kyle W Anderson, Jeffrey W Hudgens, Jason J Guo, Mahmoud L Nasr, Nikolai Zvonok, Kiran Vemuri and 2 more

Open access · goldAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Scientific reports, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.

0numbers the graph read from it
0cells of the map it votes in
10citing papers in PubMed
1.4field-weighted citation impact, top 19% of its field
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

10 citing papers in PubMed, 17 citations in OpenAlex.

  1. Article
  2. Article
  3. Article
  4. Inverse effects of APOC2 and ANGPTL4 on the conformational dynamics of lid-anchoring structures in lipoprotein lipase.Proceedings of the National Academy of Sciences of the United States of America · 2023
    Article
  5. Mapping allosteric pathway in NIa-Pro using computational approach.Quantitative biology (Beijing, China) · 2023
    Article
  6. Article
  7. Review
  8. Article
  9. Review
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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

12 authors at 6 institutions in 2 countries.

Sergiy TyukhtenkoCenter for Drug Discovery and Departments of Pharmaceutical Sciences and Chemistry and Chemical Biology, Northeastern University, Boston, MA, 02115-5000, USA. s.tyukhtenko@northeastern.edu.
Xiaoyu MaCenter for Drug Discovery and Departments of Pharmaceutical Sciences and Chemistry and Chemical Biology, Northeastern University, Boston, MA, 02115-5000, USA.
Girija RajarshiCenter for Drug Discovery and Departments of Pharmaceutical Sciences and Chemistry and Chemical Biology, Northeastern University, Boston, MA, 02115-5000, USA.
Ioannis KarageorgosBioProcess Measurements Group, Biomolecular Measurement Division, National Institute of Standards & Technology, Rockville, MD, 20850, USA.
Kyle W AndersonBioProcess Measurements Group, Biomolecular Measurement Division, National Institute of Standards & Technology, Rockville, MD, 20850, USA.
Jeffrey W HudgensBioProcess Measurements Group, Biomolecular Measurement Division, National Institute of Standards & Technology, Rockville, MD, 20850, USA.
Jason J GuoCenter for Drug Discovery and Departments of Pharmaceutical Sciences and Chemistry and Chemical Biology, Northeastern University, Boston, MA, 02115-5000, USA.
Mahmoud L NasrDepartment of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, 02115, USA.
Nikolai ZvonokCenter for Drug Discovery and Departments of Pharmaceutical Sciences and Chemistry and Chemical Biology, Northeastern University, Boston, MA, 02115-5000, USA.
Kiran VemuriCenter for Drug Discovery and Departments of Pharmaceutical Sciences and Chemistry and Chemical Biology, Northeastern University, Boston, MA, 02115-5000, USA.
Gerhard WagnerDepartment of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, 02115, USA.
Alexandros MakriyannisCenter for Drug Discovery and Departments of Pharmaceutical Sciences and Chemistry and Chemical Biology, Northeastern University, Boston, MA, 02115-5000, USA. a.makriyannis@northeastern.edu.
Northeastern University · USAdvanced Bioscience Laboratories (United States) · USBrigham and Women's Hospital · USEastern University · BDHarvard University · USMaterial Measurement Laboratory · US

Funding

MOLECULAR BASIS OF CANNABINOID ACTIVITYR01DA003801 · NIDA · UNIVERSITY OF CONNECTICUT STORRS · PI MAKRIYANNIS, ALEXANDROS · 1985 to 2017
$2.5M
Antidotes for Acute Cannabinoid IntoxicationR21DA045882 · NIDA · NORTHEASTERN UNIVERSITY · PI MAKRIYANNIS, ALEXANDROS · 2018 to 2019
$416k
NIDA NIH HHS R01 DA003801NIDA NIH HHS R01DA003801NIDA NIH HHS R21 DA045882NIDA NIH HHS R21DA045882
6 · The paper itself

Abstract

Inhibition of human Monoacylglycerol Lipase (hMGL) offers a novel approach for treating neurological diseases. The design of inhibitors, targeting active-inactive conformational transitions of the enzyme, can be aided by understanding the interplay between structure and dynamics. Here, we report the effects of mutations within the catalytic triad on structure, conformational gating and dynamics of hMGL by combining kinetics, NMR, and HDX-MS data with metadynamics simulations. We found that point mutations alter delicate conformational equilibria between active and inactive states. HDX-MS reveals regions of the hMGL that become substantially more dynamic upon substitution of catalytic acid Asp-239 by alanine. These regions, located far from the catalytic triad, include not only loops but also rigid α-helixes and β-strands, suggesting their involvement in allosteric regulation as channels for long-range signal transmission. The results identify the existence of a preorganized global communication network comprising of tertiary (residue-residue contacts) and quaternary (rigid-body contacts) networks that mediate robust, rapid intraprotein signal transmission. Catalytic Asp-239 controls hMGL allosteric communications and may be considered as an essential residue for the integration and transmission of information to enzymes' remote regions, in addition to its well-known role to facilitate Ser-122 activation. Our findings may assist in the identification of new druggable sites in hMGL.

Indexed as

Allosteric RegulationCatalysisHumansKineticsMagnetic Resonance SpectroscopyModels, MolecularMolecular Dynamics SimulationMonoacylglycerol LipasesMutationMutation, MissenseProtein ConformationStructure-Activity RelationshipMonoacylglycerol Lipases

Identifiers

PMID33116203
PMCPMC7595040
OpenAlexW3097371853

What OpenQuestion holds

Textmetadata
LicenceCC BY
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.