The Phyre2 web portal for protein modeling, prediction and analysis

Kelley, Lawrence A.; Mezulis, Stefans; Yates, Christopher M.; Wass, Mark N.; Sternberg, Michael J.E.

doi:10.1038/nprot.2015.053

Cited by 8,944 publications

(7,698 citation statements)

References 36 publications

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“…Pfu GlyRS-IIA was modeled to human GlyRS-IIA (PDB 4KQE) [28] using the program Phyre2 [45,46]. Atomic coordinates were refined using the YASARA energy minimization server (http://www.yasara.org/minimizationserver.htm).…”

Section: Methodsmentioning

confidence: 99%

Aminoacyl-tRNA synthetase evolution and sectoring of the genetic code

2018

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The genetic code sectored via tRNA charging errors, and the code progressed toward closure and universality because of evolution of aminoacyl-tRNA synthetase (aaRS) fidelity and translational fidelity mechanisms. Class I and class II aaRS folds are identified as homologs. From sequence alignments, a structurally conserved Zn-binding domain common to class I and class II aaRS was identified. A model for the class I and class II aaRS alternate folding pathways is posited. Five mechanisms toward code closure are highlighted: 1) aaRS proofreading to remove mischarged amino acids from tRNA; 2) accurate aaRS active site specification of amino acid substrates; 3) aaRS-tRNA anticodon recognition; 4) conformational coupling proofreading of the anticodon-codon interaction; and 5) deamination of tRNA wobble adenine to inosine. In tRNA anticodons there is strong wobble sequence preference that results in a broader spectrum of contacts to synonymous mRNA codon wobble bases. Adenine is excluded from the anticodon wobble position of tRNA unless it is modified to inosine. Uracil is generally preferred to cytosine in the tRNA anticodon wobble position. Because of wobble ambiguity when tRNA reads mRNA, the maximal coding capacity of the three nucleotide code read by tRNA is 31 amino acids + stops.

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Section: Methodsmentioning

confidence: 99%

Aminoacyl-tRNA synthetase evolution and sectoring of the genetic code

2018

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“…We searched structure models for human CaMKII α and β using Phyre223 and selected the two crystal structures: the low‐resolution (3.55 Å) crystal structure covering most part of the full‐length human CaMKII α (PDB code 3soa) and the high‐resolution (2.3 Å) one covering the kinase domain and the regulatory segment of human CaMKII α (PDB code 2vz6). The FoldX calculation was performed using the latter crystal structure.…”

Section: Methodsmentioning

confidence: 99%

De novo variants in CAMK2A and CAMK2B cause neurodevelopmental disorders

Akita

Aoto

Kato

et al. 2018

Ann Clin Transl Neurol

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Objective α (CAMK2A) and β (CAMK2B) isoforms of Calcium/calmodulin‐dependent protein kinase II (CaMKII) play a pivotal role in neuronal plasticity and in learning and memory processes in the brain. Here, we explore the possible involvement of α‐ and β‐CaMKII variants in neurodevelopmental disorders.MethodsWhole‐exome sequencing was performed for 976 individuals with intellectual disability, developmental delay, and epilepsy. The effect of CAMK2A and CAMK2B variants on CaMKII structure and firing of neurons was evaluated by computational structural analysis, immunoblotting, and electrophysiological analysis.ResultsWe identified a total of five de novo CAMK2A and CAMK2B variants in three and two individuals, respectively. Seizures were common to three individuals with CAMK2A variants. Using a minigene splicing assay, we demonstrated that a splice site variant caused skipping of exon 11 leading to an in‐frame deletion of the regulatory segment of CaMKII α. By structural analysis, four missense variants are predicted to impair the interaction between the kinase domain and the regulatory segment responsible for the autoinhibition of its kinase activity. The Thr286/Thr287 phosphorylation as a result of release from autoinhibition was increased in three mutants when the mutants were stably expressed in Neuro‐2a neuroblastoma cells. Expression of a CaMKII α mutant in primary hippocampal neurons significantly increased A‐type K+ currents, which facilitated spike repolarization of single action potentials.InterpretationOur data highlight the importance of CaMKII α and CaMKII β and their autoinhibitory regulation in human brain function, and suggest the enhancement of A‐type K+ currents as a possible pathophysiological basis.

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“…A theoretical model of the TetB tertiary structure was created using Phyre2 based upon its sequence homology with the E. coli MFS transporter YajR (PBD ID: 3wdo; Kelley et al , 2015). YajR was selected for the homology model due to its high sequence similarity to TetB (32%) with the resulting model displaying 100% confidence according to Phyre2.…”

Section: Methodsmentioning

confidence: 99%

Using cellular fitness to map the structure and function of a major facilitator superfamily effluxer

Perez

Gomez

Kalvapalle

et al. 2017

Molecular Systems Biology

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The major facilitator superfamily (MFS) effluxers are prominent mediators of antimicrobial resistance. The biochemical characterization of MFS proteins is hindered by their complex membrane environment that makes in vitro biochemical analysis challenging. Since the physicochemical properties of proteins drive the fitness of an organism, we posed the question of whether we could reverse that relationship and derive meaningful biochemical parameters for a single protein simply from fitness changes it confers under varying strengths of selection. Here, we present a physiological model that uses cellular fitness as a proxy to predict the biochemical properties of the MFS tetracycline efflux pump, TetB, and a family of single amino acid variants. We determined two lumped biochemical parameters roughly describing K m and V max for TetB and variants. Including in vivo protein levels into our model allowed for more specified prediction of pump parameters relating to substrate binding affinity and pumping efficiency for TetB and variants. We further demonstrated the general utility of our model by solely using fitness to assay a library of tet(B) variants and estimate their biochemical properties.

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The Phyre2 web portal for protein modeling, prediction and analysis

Cited by 8,944 publications

References 36 publications

Aminoacyl-tRNA synthetase evolution and sectoring of the genetic code

Aminoacyl-tRNA synthetase evolution and sectoring of the genetic code

De novo variants in CAMK2A and CAMK2B cause neurodevelopmental disorders

Using cellular fitness to map the structure and function of a major facilitator superfamily effluxer

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