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13:02
Production, Crystallization, and Structure Determination of the IKK-binding Domain of NEMO
Published on: December 28, 2019
Optimizing structural modeling for a specific protein scaffold: knottins or inhibitor cystine knots
1CNRS, UMR5048, Université Montpellier 1 et 2, Centre de Biochimie Structurale, 34090 Montpellier, France. Jerome.Gracy@cbs.cnrs.fr
BMC Bioinformatics
|October 30, 2010
Summary
We developed an automated method to predict knottin protein structures, achieving high accuracy even with low sequence identity. This new tool provides a database of 1621 structural models for knottin sequences, aiding drug design and protein analysis.
Area of Science:
- Protein structure prediction
- Computational biology
- Drug design
Background:
- Knottins are small, stable proteins with diverse sequences, structures, and functions, presenting significant drug design potential.
- Despite sequence variability (15-40% identity), knottins share a common knotted disulfide core, with loop regions driving structural diversity.
- Predicting structural models for all knottin sequences is crucial for analyzing interaction sites and understanding their structural-functional relationships.
Purpose of the Study:
- To develop and optimize an automated homology modeling procedure for predicting three-dimensional knottin structures.
- To create a comprehensive database of structural models for all known knottin sequences.
- To provide a user-friendly tool for interactive knottin structure prediction.
Main Methods:
- Designed an automated homology modeling pipeline, optimizing template selection, alignment, structural constraint extraction, model building, evaluation, and refinement.
- Validated the procedure against a test set of knottins with known structures.
- Developed a web server and a structure prediction module (Knoter1D3D) within a protein analysis toolkit (PAT).
Main Results:
- Achieved high accuracy in predicted models, with deviations between 1.50 and 1.96 Å from native structures at 50% and 10% sequence identity, respectively.
- Demonstrated an improvement of 0.74–1.17 Å compared to basic homology modeling using a single template.
- Generated and made publicly accessible a database of 1621 structural models for all known knottin sequences via a web server.
Conclusions:
- Systematic homology modeling can be effectively applied to diverse protein families like knottins.
- Model accuracy at low sequence identity is significantly enhanced by optimizing the modeling procedure, using multiple templates, and incorporating conserved structural features as restraints.
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