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Disulfide bond plasticity in epidermal growth factor.
B A Sampoli Benitez1, E A Komives
1Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla 92093-0359, USA.
Proteins
|May 17, 2000
Summary
Epidermal growth factor (EGF) domains can adopt multiple disulfide-bonding patterns, not just the common one. This structural flexibility suggests significant implications for EGF protein function and bioactivity.
Area of Science:
- Biochemistry
- Structural Biology
- Molecular Biology
Background:
- Epidermal growth factor (EGF) domains typically exhibit a conserved (1-3,2-4,5-6) disulfide-bonding pattern.
- This pattern is prevalent across diverse EGF-like domains despite sequence variability.
Purpose of the Study:
- To investigate the structural and energetic feasibility of alternative disulfide-bonding patterns in EGF.
- To determine if the EGF fold can accommodate isomers with retained bioactivity.
Main Methods:
- Computational modeling of murine EGF with seven altered disulfide-bonding patterns.
- Structure calculations incorporated high-resolution restraints from existing data.
- Analysis included distance and dihedral violations, XPLOR energies, Procheck statistics, and RMSDs.
Main Results:
- Two novel disulfide-bonding patterns, (1-2,3-4,5-6) and (1-3,2-5,4-6), satisfied all structural restraints, indistinguishable from the native pattern.
- Other patterns met distance restraints but exhibited cysteine dihedral violations.
- All seven calculated isomers showed high structural similarity to native EGF (1.5-2 Å RMSD).
Conclusions:
- The EGF backbone fold possesses inherent flexibility, accommodating multiple disulfide-bonding patterns.
- This adaptability may explain the significant bioactivity observed in EGF disulfide bond isomers.
- Suggests a broader understanding of EGF structure-function relationships is possible.