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X-Ray Crystallography to Study the Oligomeric State Transition of the Thermotoga maritima M42 Aminopeptidase TmPep1050
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Human aminolevulinate synthase structure reveals a eukaryotic-specific autoinhibitory loop regulating substrate
Henry J Bailey1, Gustavo A Bezerra1, Jason R Marcero2
1Structural Genomics Consortium, Nuffield Department of Medicine, University of Oxford, Oxford, OX3 7DQ, UK.
Nature Communications
|June 6, 2020
Summary
Human ALAS2 crystal structure reveals its C-terminal extension autoinhibits the enzyme. This finding explains X-linked protoporphyria and offers a strategy for developing ALAS2 inhibitors for treating porphyria.
Area of Science:
- Biochemistry
- Structural Biology
- Genetics
Background:
- 5'-aminolevulinate synthase (ALAS) is crucial for heme biosynthesis.
- Mutations in ALAS2 cause X-linked protoporphyria (XLP), a disorder of toxic heme intermediate accumulation.
- The C-terminal (Ct) extension of ALAS2 is unique to higher eukaryotes and implicated in XLP pathogenesis.
Purpose of the Study:
- To determine the crystal structure of human ALAS2.
- To elucidate the role of the Ct-extension in ALAS2 regulation and XLP.
- To identify potential therapeutic targets for ALAS2 inhibition.
Main Methods:
- X-ray crystallography of human ALAS2.
- Molecular dynamics simulations.
- Crystallography-based fragment screening.
Main Results:
- The ALAS2 crystal structure shows the Ct-extension inhibits the active site, preventing substrate binding.
- Molecular dynamics simulations support the autoinhibitory role of the Ct-extension.
- Fragment screening identified inhibitors targeting the Ct-extension, modulating its dynamics and ALAS2 activity.
Conclusions:
- The Ct-extension acts as an autoinhibitory domain in ALAS2.
- Ct-extension deletions in XLP relieve autoinhibition, leading to increased ALAS2 activity.
- ALAS2 inhibitors targeting the Ct-extension are potential therapeutic agents for porphyria.
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