SMS 2.0: An Updated Database to Study the Structural Plasticity of Short Peptide Fragments in Non-redundant Proteins
The function of a protein molecule is greatly influenced by its three-dimensional (3D) structure and therefore... more The function of a protein molecule is greatly influenced by its three-dimensional (3D) structure and therefore structure prediction will help identify its biological function. We have updated Sequence, Motif and Structure (SMS), the database of structurally rigid peptide fragments, by combining amino acid sequences and the corresponding 3D atomic coordinates of non-redundant (25%) and redundant (90%) protein chains available in the Protein Data Bank (PDB). SMS 2.0 provides information pertaining to the peptide fragments of length 5–14 residues. The entire dataset is divided into three categories, namely, same sequence motifs having similar, intermediate or dissimilar 3D structures. Further, options are provided to facilitate structural superposition using the program structural alignment of multiple proteins (STAMP) and the popular JAVA plug-in (Jmol) is deployed for visualization. In addition, functionalities are provided to search for the occurrences of the sequence motifs in other structural and sequence databases like PDB, Genome Database (GDB), Protein Information Resource (PIR) and Swiss-Prot. The updated database along with the search engine is available over the World Wide Web through the following URL http://cluster.physics.iisc.ernet.in/sms/.
Download (.pdf) BioSilicoSystems - A Multipronged approach towards analysis and representation of biological data
PhD thesis
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Molecular mechanism of dimerization of Bowman-Birk inhibitors. Pivotal role of ASP76 in the dimerzation.
Horsegram (Dolichos biflorus), a protein-rich leguminous pulse, is a crop native to Southeast Asia and tropical... more Horsegram (Dolichos biflorus), a protein-rich leguminous pulse, is a crop native to Southeast Asia and tropical Africa. The seeds contain multiple forms of Bowman-Birk type inhibitors. The major inhibitor HGI-III, from the native seed with 76 amino acid residues exists as a dimer. The amino acid sequence of three isoforms of Bowman-Birk inhibitor from germinated horsegram, designated as HGGI-I, HGGI-II, and HGGI-III, have been obtained by sequential Edman analyses of the pyridylethylated inhibitors and peptides derived therefrom by enzymatic and chemical cleavage. The HGGIs are monomers, comprising of 66, 65, and 60 amino acid residues, respectively. HGGI-III from the germinated seed differs from the native seed inhibitor in the physiological deletion of a dodecapeptide at the amino terminus and a tetrapeptide, -SHDD, at the carboxyl terminus. The study of the state of association of HGI-III, by size-exclusion chromatography and SDS-PAGE in the presence of 1 mM ZnCl2, has revealed the role of charged interactions in the monomer <--> dimer equilibria. Chemical modification studies of Lys and Arg have confirmed the role of charge interactions in the above equilibria. These results support the premise that a unique interaction, which stabilizes the dimer, is the cause of self-association in the inhibitors. This interaction in HGI-III involves the epsilon-amino group of the Lys24 (P1 residue) at the first reactive site of one monomer and the carboxyl of an Asp86 at the carboxyl terminus of the second monomer. Identification of the role of these individual amino acids in the structure and stability of the dimer was accomplished by chemical modifications, multiple sequence alignment of legume Bowman-Birk inhibitors, and homology modeling. The state of association may also influence the physiological and functional role of these inhibitors
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Co-conserved features associated with cis regulation of ErbB tyrosine kinases
The epidermal growth factor receptor kinases, or ErbB kinases, belong to a large sub-group of receptor tyrosine... more
The epidermal growth factor receptor kinases, or ErbB kinases, belong to a large sub-group of receptor tyrosine kinases (RTKs), which share a conserved catalytic core. The catalytic core of ErbB kinases have functionally diverged from other RTKs in that they are activated by a unique allosteric mechanism that involves specific interactions between the kinase core and the flanking Juxtamembrane (JM) and COOH-terminal tail (C-terminal tail). Although extensive studies on ErbB and related tyrosine kinases have provided important insights into the structural basis for ErbB kinase functional divergence, the sequence features that contribute to the unique regulation of ErbB kinases have not been systematically explored.
Methodology/Principal Findings
In this study, we use a Bayesian approach to identify the selective sequence constraints that most distinguish ErbB kinases from other receptor tyrosine kinases. We find that strong ErbB kinase-specific constraints are imposed on residues that tether the JM and C-terminal tail to key functional regions of the kinase core. A conserved RIxKExE motif in the JM-kinase linker region and a glutamine in the inter-lobe linker are identified as two of the most distinguishing features of the ErbB family. While the RIxKExE motif tethers the C-terminal tail to the N-lobe of the kinase domain, the glutamine tethers the C-terminal tail to hinge regions critical for inter-lobe movement. Comparison of the active and inactive crystal structures of ErbB kinases indicates that the identified residues are conformationally malleable and can potentially contribute to the cis regulation of the kinase core by the JM and C-terminal tail. ErbB3, and EGFR orthologs in sponges and parasitic worms, diverge from some of the canonical ErbB features, providing insights into sub-family and lineage-specific functional specialization.
Our analysis pinpoints key residues for mutational analysis, and provides new clues to cancer mutations that alter the canonical modes of ErbB kinase regulation
Structural and evolutionary divergence of eukaryotic protein kinases in Apicomplexa
BACKGROUND: The Apicomplexa constitute an evolutionarily divergent phylum of protozoan pathogens responsible for... more
BACKGROUND: The Apicomplexa constitute an evolutionarily divergent phylum of protozoan pathogens responsible for widespread parasitic diseases such as malaria and toxoplasmosis. Many cellular functions in these medically important organisms are controlled by protein kinases, which have emerged as promising drug targets for parasitic diseases. However, an incomplete understanding of how apicomplexan kinases structurally and mechanistically differ from their host counterparts has hindered drug development efforts to target parasite kinases.
RESULTS: We used the wealth of sequence data recently made available for 15 apicomplexan species to identify the kinome of each species and quantify the evolutionary constraints imposed on each family of apicomplexan kinases. Our analysis revealed lineage-specific adaptations in selected families, namely cyclin-dependent kinase (CDK), calcium-dependent protein kinase (CDPK) and CLK/LAMMER, which have been identified as important in the pathogenesis of these organisms. Bayesian analysis of selective constraints imposed on these families identified the sequence and structural features that most distinguish apicomplexan protein kinases from their homologs in model organisms and other eukaryotes. In particular, in a subfamily of CDKs orthologous to Plasmodium falciparum crk-5, the activation loop contains a novel PTxC motif which is absent from all CDKs outside Apicomplexa. Our analysis also suggests a convergent mode of regulation in a subset of apicomplexan CDPKs and mammalian MAPKs involving a commonly conserved arginine in the C helix. In all recognized apicomplexan CLKs, we find a set of co-conserved residues involved in substrate recognition and docking that are distinct from metazoan CLKs.
CONCLUSIONS: We pinpoint key conserved residues that can be predicted to mediate functional differences from eukaryotic homologs in three identified kinase families. We discuss the structural, functional and evolutionary implications of these lineage-specific variations and propose specific hypotheses for experimental investigation. The apicomplexan-specific kinase features reported in this study can be used in the design of selective kinase inhibitors.