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Published on: September 21, 2011
Substrate binding process and mechanistic functioning of type 1 11β-hydroxysteroid dehydrogenase from enhanced
Angelo D Favia1, Matteo Masetti, Maurizio Recanatini
1Drug Discovery and Development Department, Istituto Italiano di Tecnologia, Genoa, Italy. angelo.favia@iit.it
Plos One
|October 4, 2011
Summary
Type 1 11β-hydroxysteroid dehydrogenase (11β-HSD-1) dynamic behavior was simulated upon substrate binding. This study reveals key insights into enzyme-substrate interactions, dimerisation, and ligand recognition.
Area of Science:
- Biochemistry
- Molecular Biology
- Structural Biology
Background:
- Type 1 11β-hydroxysteroid dehydrogenase (11β-HSD-1) regulates glucocorticoid balance by converting cortisone to cortisol.
- X-ray structures and experimental data have elucidated many functional aspects of 11β-HSD-1.
- A comprehensive understanding of 11β-HSD-1's dynamic behavior during substrate binding is currently lacking.
Purpose of the Study:
- To investigate the dynamic behavior of 11β-HSD-1 during substrate binding using computational methods.
- To elucidate the molecular mechanisms underlying the enzyme-substrate relationship for 11β-HSD-1.
- To provide a detailed description of 11β-HSD-1's dynamic interactions with its natural substrate, cortisone.
Main Methods:
- Molecular docking of cortisone into the catalytic site of wild-type and Y177A mutant 11β-HSD-1.
- Steered molecular dynamics and metadynamics simulations to model cortisone undocking from 11β-HSD-1.
- Computational analysis of enzyme-substrate interactions at a molecular level.
Main Results:
- The study identified the molecular basis for the functional dimerisation of 11β-HSD-1.
- The critical role of the Y177 residue in the cortisone binding event was highlighted.
- Key insights were gained into the regulation of active site solvation and the function of the S228-P237 loop in ligand recognition.
Conclusions:
- The computational simulations provide a detailed molecular-level understanding of 11β-HSD-1's dynamic response to substrate binding.
- The findings clarify the structural and dynamic determinants of 11β-HSD-1 activity and substrate interaction.
- This work enhances our knowledge of glucocorticoid metabolism regulation by 11β-HSD-1.
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