Functional identification of unknown proteins discovered in sequence and structural genome projects is a major challenge for postgenomic biology. This Program Project develops an integrated sequence-structure based strategy for functional assignment of unknown proteins by predicting the substrate specificities of unknown members of the functionally diverse enolase and amidohydrolase superfamilies that share the ubiquitous (beta/alpha)8-fold. The unimolecular reactions catalyzed by members of each of these superfamilies share common mechanistic strategies, so the success of specificity predictions can be readily evaluated. This project integrates expertise in functional enzymology (protein purification, measurement of function, and determination of mechanism), structural enzymology (high resolution x-ray structural analysis), and, for the first time, computational biology (bioinformatics, homology modeling, and molecular docking). These diverse, but complementary, approaches for obtaining clues regarding the identity of the substrate will efficiently restrict the identities of the substrates for unknown members of these superfamilies. The integrated strategy developed in this Project will be generally applicable to deciphering the ligand specificities of any functionally unknown protein. The goals of this project extend the contribution of the Protein Structure Initiative funded by NIGMS that seeks to obtain structures for proteins of unknown function that will allow reliable homology modeling.
| Holliday, Gemma L; Brown, Shoshana D; Akiva, Eyal et al. (2017) Biocuration in the structure-function linkage database: the anatomy of a superfamily. Database (Oxford) 2017: |
| Holliday, Gemma L; Brown, Shoshana D; Akiva, Eyal et al. (2017) Biocuration in the structure-function linkage database: the anatomy of a superfamily. Database (Oxford) 2017: |
| Webb, Benjamin; Sali, Andrej (2016) Comparative Protein Structure Modeling Using MODELLER. Curr Protoc Bioinformatics 54:5.6.1-5.6.37 |
| Vladimirova, Anna; Patskovsky, Yury; Fedorov, Alexander A et al. (2016) Substrate Distortion and the Catalytic Reaction Mechanism of 5-Carboxyvanillate Decarboxylase. J Am Chem Soc 138:826-36 |
| Fedorov, Alexander A; MartÃ-Arbona, Ricardo; Nemmara, Venkatesh V et al. (2015) Structure of N-formimino-L-glutamate iminohydrolase from Pseudomonas aeruginosa. Biochemistry 54:890-7 |
| Xiang, Dao Feng; Patskovsky, Yury; Nemmara, Venkatesh V et al. (2015) Function discovery and structural characterization of a methylphosphonate esterase. Biochemistry 54:2919-30 |
| Zhang, Xinshuai; Kumar, Ritesh; Vetting, Matthew W et al. (2015) A unique cis-3-hydroxy-l-proline dehydratase in the enolase superfamily. J Am Chem Soc 137:1388-91 |
| Akiva, Eyal; Brown, Shoshana; Almonacid, Daniel E et al. (2014) The Structure-Function Linkage Database. Nucleic Acids Res 42:D521-30 |
| Korczynska, Magdalena; Xiang, Dao Feng; Zhang, Zhening et al. (2014) Functional annotation and structural characterization of a novel lactonase hydrolyzing D-xylono-1,4-lactone-5-phosphate and L-arabino-1,4-lactone-5-phosphate. Biochemistry 53:4727-38 |
| Brown, Shoshana; Babbitt, Patricia (2014) Using the structure-function linkage database to characterize functional domains in enzymes. Curr Protoc Bioinformatics 48:2.10.1-16 |
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