Dataset Information

Modeling and structural analysis of human Guanine nucleotide-binding protein-like 3,nucleostemin.

ABSTRACT: Human GNL3 (nucleostemin) is a recently discovered nucleolar protein with pivotal functions in maintaining genomic integrity and determining cell fates of various normal and cancerous stem cells. Recent reports suggest that targeting this GTP-binding protein may have therapeutic value in cancer. Although, sequence analyzing revealed that nucleostemin (NS) comprises 5 permuted GTP-binding motifs, a crystal structure for this protein is missing at Protein Data Bank (PDB). Obviously, any attempt for predicting of NS structure can further our knowledge on its functional sites and subsequently designing molecular inhibitors. Herein, we used bioinformatics tools and could model 262 amino acids of NS (132-393 aa). Initial models were built by MODELLER, refined with Scwrl4 program, and validated with ProsA and Jcsc databases as well as PSVS software. Then, the best quality model was chosen for motif and domain analyzing by Pfam, PROSITE and PRINTS. The final model was visualized by vmd program. This predicted model may pave the way for next studies regarding ligand binding states and interaction sites as well as screening of databases for potential inhibitors.

SUBMITTER: Nazmi F

PROVIDER: S-EPMC4546995 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Modeling and structural analysis of human Guanine nucleotide-binding protein-like 3,nucleostemin.

Nazmi Farinaz F Moosavi Mohammad Amin MA Rahmati Marveh M Hoessinpour-Feizi Mohammad Ali MA

Bioinformation 20150731 7

Human GNL3 (nucleostemin) is a recently discovered nucleolar protein with pivotal functions in maintaining genomic integrity and determining cell fates of various normal and cancerous stem cells. Recent reports suggest that targeting this GTP-binding protein may have therapeutic value in cancer. Although, sequence analyzing revealed that nucleostemin (NS) comprises 5 permuted GTP-binding motifs, a crystal structure for this protein is missing at Protein Data Bank (PDB). Obviously, any attempt fo ...[more]

PMID: 26339152

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Project description:We have presented a new protein-protein docking approach to model heterodimeric structures based on the conformations of the monomeric units. The conventional modeling method relies on superimposing two monomeric structures onto the crystal structure of a homologous protein dimer. The resulting structure may exhibit severe backbone clashes at the dimeric interface depending on the backbone dissimilarity between the target and template proteins. Our method overcomes the backbone clashing problem and requires no a priori knowledge of the dimeric structure of a homologous protein. Here we used human Cystic Fibrosis Transmembrane conductance Regulator (CFTR), a chloride channel whose dysfunction causes cystic fibrosis, for illustration. The two intracellular nucleotide-binding domains (NBDs) of CFTR control the opening and closing of the channel. Yet, the structure of the CFTR's NBD1-NBD2 complex has not been experimentally determined. Thus, correct modeling of this heterodimeric structure is valuable for understanding CFTR functions and would have potential applications for drug design for cystic fibrosis treatment. Based on the crystal structure of human CFTR's NBD1, we constructed a model of the NBD1-NBD2 complex. The constructed model is consistent with the dimeric mode observed in the crystal structures of other ABC transporters. To verify our structural model, an ATP substrate was docked into the nucleotide-binding site. The predicted binding mode shows consistency with related crystallographic findings and CFTR functional studies. Finally, genistein, an agent that enhances CFTR activity, though the mechanism for such enhancement is unclear, was docked to the model. Our predictions agreed with genistein's bell-shaped dose-response relationship. Potential mutagenesis experiments were proposed for understanding the potentiation mechanism of genistein and for providing insightful information for drug design targeting at CFTR. The method used in this study can be applied to modeling studies of other dimeric protein structures.

Dataset Information

Modeling and structural analysis of human Guanine nucleotide-binding protein-like 3,nucleostemin.

Publications

Modeling and structural analysis of human Guanine nucleotide-binding protein-like 3,nucleostemin.

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