Protein Structure Modeling with MODELLER

Eswar, Narayanan; Eramian, David; Webb, Ben; Shen, Min-Yi; Šali, Andrej

doi:10.1007/978-1-60327-058-8_8

Cited by 1,289 publications

(820 citation statements)

References 57 publications

(4 reference statements)

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“…Modeller9v7 [16], Schrodinger 2009 [17], and online bioinformatics resources were employed to propose the research findings.…”

Section: Hardware and Softwarementioning

confidence: 99%

“…The BLASTP alignment was further refined using ClustalX [25]. The sequence alignment file was used as input to the Modeller9v7 [16] to construct homology models for L. interrogans MurD in complex with UMA. A bundle of 20 models from random generation of the starting structure was calculated, and the best model (structure with lowest DOPE score) was subjected for further analysis.…”

Section: Homology Modeling Of Murdmentioning

confidence: 99%

“…The stereochemical parameters of the energy minimized MurD model were assessed by Procheck, ProSA, ProQ [27][28][29], and Profile 3D [16]. Procheck and ProSA are optimized to find native structures, while ProQ is a neural network-based predictor that is based on a number of structural features to predict the quality of a protein model.…”

Section: Evaluation Of Model Qualitymentioning

confidence: 99%

“…Procheck and ProSA are optimized to find native structures, while ProQ is a neural network-based predictor that is based on a number of structural features to predict the quality of a protein model. The target and template Density Optimization Potential Energy (DOPE) profiles were plotted using gnuplot (http:// www.gnuplot.info/), and Modeller SuperPose command was used to superimpose the 3D structures of template and target [16]. The developed 3D model of L. interrogans MurD was submitted to Protein Model Data Base (PMDB) [30], which collects 3D models obtained by structure prediction methods.…”

Section: Evaluation Of Model Qualitymentioning

confidence: 99%

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Virtual screening for potential inhibitors of homology modeled Leptospira interrogans MurD ligase

2010

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The life-threatening infections caused by Leptospira serovars remain a global challenge since long time. Prevention of infection by controlling environmental factors being difficult to practice in developing countries, there is a need for designing potent anti-leptospirosis drugs. ATP-dependent MurD involved in biosynthesis of peptidoglycan was identified as common drug target among pathogenic Leptospira serovars through subtractive genomic approach. Peptidoglycan biosynthesis pathway being unique to bacteria and absent in host represents promising target for antimicrobial drug discovery. Thus, MurD 3D models were generated using crystal structures of 1EEH and 2JFF as templates in Modeller9v7. Structural refinement and energy minimization of the model was carried out in Maestro 9.0 applying OPLS-AA 2001 force field and was evaluated through Procheck, ProSA, PROQ, and Profile 3D. The active site residues were confirmed from the models in complex with substrate and inhibitor. Four published MurD inhibitors (two phosphinics, one sulfonamide, and one benzene 1,3-dicarbixylic acid derivative) were queried against more than one million entries of Ligand.Info Meta-Database to generate in-house library of 1,496 MurD inhibitor analogs. Our approach of virtual screening of the best-ranked compounds with pharmacokinetics property prediction has provided 17 novel MurD inhibitors for developing anti-leptospirosis drug targeting peptidoglycan biosynthesis pathway.

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“…Modeller9v7 [16], Schrodinger 2009 [17], and online bioinformatics resources were employed to propose the research findings.…”

Section: Hardware and Softwarementioning

confidence: 99%

Section: Homology Modeling Of Murdmentioning

confidence: 99%

Section: Evaluation Of Model Qualitymentioning

confidence: 99%

Section: Evaluation Of Model Qualitymentioning

confidence: 99%

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Virtual screening for potential inhibitors of homology modeled Leptospira interrogans MurD ligase

2010

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“…With continous emergence of new sequences of proteins involved in various diseases, our desire to predict their structures in order to understand their function is greatly elevated. Hence, quick and accurate strategies for computational modeling have been in use in past couple of years [12,24,29,43]. Recently, a computational study has been done which sheds light on how a protein GEF mediates the activation of a small G protein Arf1 [25].…”

Section: Introductionmentioning

confidence: 99%

Insights into structure and function of SHIP2-SH2: homology modeling, docking, and molecular dynamics study

Saqib

Siddiqi

2011

J Chem Biol

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SRC homology 2 (SH2)-containing inositol 5′-phosphatase protein (SHIP2) is a potential target for type 2 diabetes. Its ability to dephosphorylate the lipid messenger phosphatidylinositol 3,4,5-trisphosphate [PtdIns(3,4,5)P3], important for insulin signaling, makes it an important target against type 2 diabetes. The insulin-induced SHIP2 interaction with Shc is very important for the membrane localization and functioning of SHIP2. There is a bidentate relationship between the two proteins where two domains each from SHIP2 and Shc are involved in mutual binding. However in the present study, the SHIP2-SH2 domain binding with the phosphorylated tyrosine 317 on the collagen-homology (CH) domain of Shc, has been studied due to the indispensability of this interaction in SHIP2 localization. In the absence of the crystal structure of SHIP2-SH2, its structural model was developed followed by tracking its molecular interactions with Shc through molecular docking and dynamics studies. This study revealed much about the structural interactions between the SHIP2-SH2 and Shc-CH. Finally, docking study of a nonpeptide inhibitor into the SHIP2-SH2 domain further confirmed the structural interactions involved in ligand binding and also proposed the inhibitor as a major starting point against SHIP2-SH2 inhibition. The insights gained from the current study should prove useful in the design of more potent inhibitors against type 2 diabetes.

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An Unusual Retinal Phenotype Associated With a Novel Mutation in RHO

Audo

Friedrich²,

Mohand‐Saïd³

et al. 2010

Arch Ophthalmol

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To report a new genetic variant in the rhodopsin gene (RHO) associated with an unusual autosomal dominant retinal phenotype. Methods: Detailed phenotypic characterization was performed on affected family members spanning 4 generations, including family history, best-corrected visual acuity, fundus examination, kinetic and static perimetry, fullfield and multifocal electroretinography, fundus autofluorescence, and optical coherence tomography. For genetic testing, coding exons and flanking intronic regions of RHO were amplified with the use of polymerase chain reaction, purified, and sequenced. Cosegregation and control analysis were performed by direct sequencing of exon 3. Subsequent in silico analysis of the mutational consequence on protein function was undertaken. Results: The onset of symptoms appeared in the fourth decade of life in this family, with moderate night blindness and asymmetrical visual loss. Affected members showed patchy areas of chorioretinal atrophy with decreased electroretinographic response amplitudes for both scotopic and photopic responses but no implicit time shift, consistent with restricted disease. A novel mutation in exon 3 of RHO was identified and represents a c.620TϾA transition leading to a p.Met207Lys substitution. It cosegregated with this phenotype and was not identified in a control population. Conclusions: We report the phenotype-genotype correlation of an unusual autosomal dominant, late-onset restricted chorioretinal degeneration cosegregating with a novel RHO mutation, p.Met207Lys. A p.Met207Arg substitution has previously been reported to cause a distinct, generalized early-onset rod-cone dystrophy. Clinical Relevance: These data outline the phenotypic variability associated with RHO mutations. Depending on the localization and the amino acid substitution, patients may show congenital stationary night blindness, rod-cone dystrophy, sector retinitis pigmentosa, or localized chorioretinal atrophy.

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Protein Structure Modeling with MODELLER

Cited by 1,289 publications

References 57 publications

Virtual screening for potential inhibitors of homology modeled Leptospira interrogans MurD ligase

Virtual screening for potential inhibitors of homology modeled Leptospira interrogans MurD ligase

Insights into structure and function of SHIP2-SH2: homology modeling, docking, and molecular dynamics study

An Unusual Retinal Phenotype Associated With a Novel Mutation in RHO

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