ArticleScientific reports2018
Effects of Distal Mutations on the Structure, Dynamics and Catalysis of Human Monoacylglycerol Lipase.
Article in Scientific reports, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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Who cites it
16 citing papers in PubMed.
- Article
- Origins of Catalysis in Non-Heme Fe(II)/2-Oxoglutarate-Dependent Histone Lysine Demethylase KDM4A with Differently Methylated Histone H3 Peptides.Chemistry (Weinheim an der Bergstrasse, Germany) · 2025Article
- Non-active Site Residue in Loop L4 Alters Substrate Capture and Product Release in d-Arginine Dehydrogenase.Biochemistry · 2023Article
- Computational Insights into the Allosteric Modulation of a Phthalate-Degrading Hydrolase by Distal Mutations.Biomolecules · 2023Article
- Characterizing and explaining the impact of disease-associated mutations in proteins without known structures or structural homologs.Briefings in bioinformatics · 2022Article
- Mechanistic Modeling of Monoglyceride Lipase Covalent Modification Elucidates the Role of Leaving Group Expulsion and Discriminates Inhibitors with High and Low Potency.Journal of chemical information and modeling · 2022Article
- Leveraging intrinsic flexibility to engineer enhanced enzyme catalytic activity.Proceedings of the National Academy of Sciences of the United States of America · 2022Article
- Inhibition of triple negative breast cancer-associated inflammation, tumor growth and brain colonization by targeting monoacylglycerol lipase.Scientific reports · 2022Article
- Tyrp1 Mutant Variants Associated with OCA3: Computational Characterization of Protein Stability and Ligand Binding.International journal of molecular sciences · 2021Article
- Methemoglobin formation in mutant hemoglobin α chains: electron transfer parameters and rates.Biophysical journal · 2021Article
- Characterization of Temperature-Dependent Kinetics of Oculocutaneous Albinism-Causing Mutants of Tyrosinase.International journal of molecular sciences · 2021Article
- Conformational gating, dynamics and allostery in human monoacylglycerol lipase.Scientific reports · 2020Article
- Modeling the Role of a Flexible Loop and Active Site Side Chains in Hydride Transfer Catalyzed by Glycerol-3-phosphate Dehydrogenase.ACS catalysis · 2020Article
- A Thermolabile Phospholipase B fromBiomolecules · 2020Article
- Structural and free energy landscape of novel mutations in ribosomal protein S1 (rpsA) associated with pyrazinamide resistance.Scientific reports · 2019Article
- Structural Perspective on Revealing and Altering Molecular Functions of Genetic Variants Linked with Diseases.International journal of molecular sciences · 2019Review
Corrections and comments
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12 authors.
Funding
Abstract
An understanding of how conformational dynamics modulates function and catalysis of human monoacylglycerol lipase (hMGL), an important pharmaceutical target, can facilitate the development of novel ligands with potential therapeutic value. Here, we report the discovery and characterization of an allosteric, regulatory hMGL site comprised of residues Trp-289 and Leu-232 that reside over 18 Å away from the catalytic triad. These residues were identified as critical mediators of long-range communication and as important contributors to the integrity of the hMGL structure. Nonconservative replacements of Trp-289 or Leu-232 triggered concerted motions of structurally distinct regions with a significant conformational shift toward inactive states and dramatic loss in catalytic efficiency of the enzyme. Using a multimethod approach, we show that the dynamically relevant Trp-289 and Leu-232 residues serve as communication hubs within an allosteric protein network that controls signal propagation to the active site, and thus, regulates active-inactive interconversion of hMGL. Our findings provide new insights into the mechanism of allosteric regulation of lipase activity, in general, and may provide alternative drug design possibilities.
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