Your browser doesn't support javascript.
loading
Coevolution-based prediction of key allosteric residues for protein function regulation.
Xie, Juan; Zhang, Weilin; Zhu, Xiaolei; Deng, Minghua; Lai, Luhua.
Afiliación
  • Xie J; Center for Quantitative Biology, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, China.
  • Zhang W; BNLMS, Peking-Tsinghua Center for Life Sciences at the College of Chemistry and Molecular Engineering, Peking University, Beijing, China.
  • Zhu X; School of Sciences, Anhui Agricultural University, Hefei, China.
  • Deng M; Center for Quantitative Biology, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, China.
  • Lai L; School of Mathematical Sciences, Peking University, Beijing, China.
Elife ; 122023 02 17.
Article en En | MEDLINE | ID: mdl-36799896
ABSTRACT
Allostery is fundamental to many biological processes. Due to the distant regulation nature, how allosteric mutations, modifications, and effector binding impact protein function is difficult to forecast. In protein engineering, remote mutations cannot be rationally designed without large-scale experimental screening. Allosteric drugs have raised much attention due to their high specificity and possibility of overcoming existing drug-resistant mutations. However, optimization of allosteric compounds remains challenging. Here, we developed a novel computational method KeyAlloSite to predict allosteric site and to identify key allosteric residues (allo-residues) based on the evolutionary coupling model. We found that protein allosteric sites are strongly coupled to orthosteric site compared to non-functional sites. We further inferred key allo-residues by pairwise comparing the difference of evolutionary coupling scores of each residue in the allosteric pocket with the functional site. Our predicted key allo-residues are in accordance with previous experimental studies for typical allosteric proteins like BCR-ABL1, Tar, and PDZ3, as well as key cancer mutations. We also showed that KeyAlloSite can be used to predict key allosteric residues distant from the catalytic site that are important for enzyme catalysis. Our study demonstrates that weak coevolutionary couplings contain important information of protein allosteric regulation function. KeyAlloSite can be applied in studying the evolution of protein allosteric regulation, designing and optimizing allosteric drugs, and performing functional protein design and enzyme engineering.
Asunto(s)
Palabras clave

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Proteínas Tipo de estudio: Prognostic_studies / Risk_factors_studies Idioma: En Revista: Elife Año: 2023 Tipo del documento: Article País de afiliación: China

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Proteínas Tipo de estudio: Prognostic_studies / Risk_factors_studies Idioma: En Revista: Elife Año: 2023 Tipo del documento: Article País de afiliación: China
...