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Structural Basis of the Substrate Selectivity of Viperin
Biochemistry
|January 10, 2020
Summary
Viperin, an enzyme inhibiting viral replication, converts cytidine triphosphate (CTP) to a unique form. Structural studies reveal how viperin binds CTP and uridine triphosphate (UTP), explaining its CTP selectivity.
Area of Science:
- Biochemistry
- Structural Biology
- Virology
Background:
- Viperin is an S-adenosylmethionine (SAM) enzyme crucial for inhibiting viral replication.
- It functions by converting cytidine triphosphate (CTP) and through other mechanisms involving its N- and C-terminal domains.
Purpose of the Study:
- To elucidate the structural basis of viperin's enzymatic activity and substrate selectivity.
- To understand the role of viperin's domains in binding CTP and uridine triphosphate (UTP).
Main Methods:
- X-ray crystallography to determine structures of viperin bound to SAM analogue and nucleotides (CTP or UTP).
- Enzyme kinetics to measure reaction rates and binding affinities for CTP and UTP.
Main Results:
- Crystal structures reveal how viperin binds CTP and UTP, orienting them for radical abstraction.
- Unfavorable interactions with the uracil moiety of UTP prevent tight binding, explaining lower affinity compared to CTP.
- Nucleotide binding induces ordering of the C-terminal tail, which contains a P-loop essential for nucleotide binding.
Conclusions:
- The study explains viperin's selectivity for CTP over UTP based on structural and kinetic data.
- The C-terminal tail plays a significant structural role in binding both CTP and UTP.
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