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Dramatic and concerted conformational changes enable rhodocetin to block α2β1 integrin selectively
Johannes A Eble1, Matthew McDougall2, George L Orriss2
1Institute of Physiological Chemistry and Pathobiochemistry, University of Münster, Münster, Germany.
Plos Biology
|July 14, 2017
Summary
Rhodocetin (RC) from viper venom inhibits integrin α2β1 by reorganizing its structure upon binding. This reveals the molecular basis for blocking collagen-induced platelet aggregation, crucial for hemostasis and cancer.
Area of Science:
- Biochemistry
- Structural Biology
- Pharmacology
Background:
- Integrin α2β1 is vital for hemostasis, fibrosis, and cancer.
- Rhodocetin (RC), a venom protein, inhibits α2β1 by blocking collagen binding.
- The molecular mechanism of RC inhibition remained unclear.
Purpose of the Study:
- To elucidate the molecular structure of the rhodocetin-integrin complex.
- To understand the structural basis for rhodocetin's inhibition of α2β1 integrin.
Main Methods:
- X-ray crystallography of the RCγδ-α2A complex at 3.0 Å resolution.
- Utilized epitope-mapped antibodies and mutant α2A domain constructs.
- Employed point mutations and chemical modifications of rhodocetin.
Main Results:
- The RCγδ-α2A complex structure revealed significant RC structural reorganization upon binding.
- RC releases its αβ subunit and undergoes conformational changes.
- RCγ interacts with α2A loop 2, and RCδ contacts the closed α2A domain via helix C.
Conclusions:
- The study clarifies the molecular mechanism and specificity of rhodocetin inhibition for α2β1 integrin.
- Structural insights explain how RC blocks collagen-induced platelet aggregation.
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