An overview of tools for the validation of protein NMR structures

Vuister, Geerten W.; Fogh, Rasmus H.; Hendrickx, Pieter; Doreleijers, Jurgen F.; Gutmanas, Aleksandras

doi:10.1007/s10858-013-9750-x

Cited by 35 publications

(29 citation statements)

References 125 publications

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“…In addition the range of predicted global model reliability is 0 to 1 according to Verify 3D. Hence, Plasmodium falciparum transketolase with a global model reliability score 0.74 has all the potentials of a good quality model [57–59]. …”

Section: Discussionmentioning

confidence: 99%

Molecular-docking study of malaria drug target enzyme transketolase in Plasmodium falciparum 3D7 portends the novel approach to its treatment

Hasan

Mazumder

Chowdhury

et al. 2015

Source Code Biol Med

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BackgroundMalaria has been a major life threatening mosquito borne disease from long since. Unavailability of any effective vaccine and recent emergence of multi drug resistant strains of malaria pathogen Plasmodium falciparum continues to cause persistent deaths in the tropical and sub-tropical region. As a result, demands for new targets for more effective anti-malarial drugs are escalating. Transketolase is an enzyme of the pentose phosphate pathway; a novel pathway which is involved in energy generation and nucleic acid synthesis. Moreover, significant difference in homology between Plasmodium falciparum transketolase (Pftk) and human (Homo sapiens) transketolase makes it a suitable candidate for drug therapy. Our present study is aimed to predict the 3D structure of Plasmodium falciparum transketolase and design an inhibitor against it.ResultsThe primary and secondary structural features of the protein is calculated by ProtParam and SOPMA respectively which revealed the protein is composed of 43.3 % alpha helix and 33.04 % random coils along with 15.62 % extended strands, 8.04 % beta turns. The three dimensional structure of the transketolase is constructed using homology modeling tool MODELLAR utilizing several available transketolase structures as templates. The structure is then subjected to deep optimization and validated by structure validation tools PROCHECK, VERIFY 3D, ERRAT, QMEAN. The predicted model scored 0.74 for global model reliability in PROCHECK analysis, which ensures the quality of the model. According to VERIFY 3D the predicted model scored 0.77 which determines good environmental profile along with ERRAT score of 78.313 which is below 95 % rejection limit. Protein-protein and residue–residue interaction networks are generated by STRING and RING server respectively. CASTp server was used to analyze active sites and His 109, Asn 108 and His 515 are found to be more positive site to dock the substrate, in addition molecular docking simulation with Autodock vina determined the estimated free energy of molecular binding was of −6.6 kcal/mol for most favorable binding of 6′-Methyl-Thiamin Diphosphate.ConclusionThis predicted structure of Pftk will serve first hand in the future development of effective Pftk inhibitors with potential anti-malarial activity. However, this is a preliminary study of designing an inhibitor against Plasmodium falciparum 3D7; the results await justification by in vitro and in vivo experimentations.

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Section: Discussionmentioning

confidence: 99%

Molecular-docking study of malaria drug target enzyme transketolase in Plasmodium falciparum 3D7 portends the novel approach to its treatment

Hasan

Mazumder

Chowdhury

et al. 2015

Source Code Biol Med

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“…For evaluation purposes, we used DFIRE [28], Verify3D [29], and Procheck [30–31] programs. DFIRE is a statistical, potentialbased program that uses a distance-scaled finite ideal-gas reference state.…”

Section: Methodsmentioning

confidence: 99%

A Structured-based Model for the Decreased Activity of Ala222Val and Glu429Ala Methylenetetrahydrofolate Reductase (MTHFR) Mutants

Shahzad¹,

Hai²,

Ahmed³

et al. 2013

Bioinformation

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The structure of human Methylenetetrahydrofolate Reductase (MTHFR) is not known either by NMR or by X-ray methods. Phosphorylation seems to play an important role in the functioning of this flavoprotein. MTHFR catalyzes an irreversible reaction in homocysteine metabolism. Phosphorylation decreases the activity of MTHFR by enhancing the sensitivity of the enzyme to SAdenosylmethione. Two common polymorphisms in MTHFR, Ala222Val and Glu429Ala, can result in a number of vascular diseases. Effects of the Glu429Ala polymorphism on the structure of human MTHFR remain undetermined due to limited structural information. Hence, structural models of the MTHFR mutants were constructed using I-TASSER and assessed by PROCHECK, DFIRE and Verify3D tools. A mechanism is further suggested for the decreased activity of the Ala222Val and Glu429Ala mutants due to a decrease in number of serine phosphorylation sites using information gleaned from the molecular models. This provides insights for the understanding of structure-function relationship for MTHFR.

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“…Similarly, the per-residue RMSD is taken as a measure of local precision. Alternative measures of local or global precision include dihedral angle order parameters (DAOP) [55-57] and distance variance matrix methods [57-60] ( Fig. 1).…”

Section: Which Parts Of the Structure Should Be Validated?mentioning

confidence: 99%

“…Web-based tools described in Table 2 include the CiNG [62,63], Molprobity [11], PSVS [10,14], Vivaldi [64], and ResProx [43] servers. These, as well as other programs for NMR structure quality assessment, have been critically reviewed in a recent publication [57]. The wwPDB NMR VTF has also recommended metrics and standards for biomolecular structure quality assessment [8,9], and these guidelines are being used in developing software pipelines that will generate standardized structure quality reports for all NMR and X-ray crystal structures submitted to the wwPDB.…”

Section: Protein Structure Quality Assessment Serversmentioning

confidence: 99%

Quality assessment of protein NMR structures

Rosato

Tejero

Montelione

2013

Current Opinion in Structural Biology

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Biomolecular NMR structures are now routinely used in biology, chemistry, and bioinformatics. Methods and metrics for assessing the accuracy and precision of protein NMR structures are beginning to be standardized across the biological NMR community. These include both knowledge-based assessment metrics, parameterized from the database of protein structures, and model vs. data assessment metrics. On line servers are available that provide comprehensive protein structure quality assessment reports, and efforts are in progress by the world-wide Protein Data Bank (wwPDB) to develop a biomolecular NMR structure quality assessment pipeline as part of the structure deposition process. These quality assessment metrics and standards will aid NMR spectroscopists in determining more accurate structures, and increase the value and utility of these structures for the broad scientific community.

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An overview of tools for the validation of protein NMR structures

Cited by 35 publications

References 125 publications

Molecular-docking study of malaria drug target enzyme transketolase in Plasmodium falciparum 3D7 portends the novel approach to its treatment

Molecular-docking study of malaria drug target enzyme transketolase in Plasmodium falciparum 3D7 portends the novel approach to its treatment

A Structured-based Model for the Decreased Activity of Ala222Val and Glu429Ala Methylenetetrahydrofolate Reductase (MTHFR) Mutants

Quality assessment of protein NMR structures

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