I-TASSER: a unified platform for automated protein structure and function prediction

Roy, Ambrish; Küçükural, Alper; Zhang, Yang

doi:10.1038/nprot.2010.5

Cited by 5,777 publications

(5,180 citation statements)

References 72 publications

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“…The modelled structure of the human KCC2 (hKCC2, purple) was created based on homology modelling by I‐TASSER (Roy et al . 2010; Yang et al . 2014) using available crystal structures of prokaryotic CCC cytoplasmic tail (PDB 3G40; Warmuth et al .…”

Section: Discussionmentioning

confidence: 99%

Regulation of neuronal chloride homeostasis by neuromodulators

Mahadevan

Woodin

2016

The Journal of Physiology

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KCC2 is the central regulator of neuronal Cl− homeostasis, and is critical for enabling strong hyperpolarizing synaptic inhibition in the mature brain. KCC2 hypofunction results in decreased inhibition and increased network hyperexcitability that underlies numerous disease states including epilepsy, neuropathic pain and neuropsychiatric disorders. The current holy grail of KCC2 biology is to identify how we can rescue KCC2 hypofunction in order to restore physiological levels of synaptic inhibition and neuronal network activity. It is becoming increasingly clear that diverse cellular signals regulate KCC2 surface expression and function including neurotransmitters and neuromodulators. In the present review we explore the existing evidence that G‐protein‐coupled receptor (GPCR) signalling can regulate KCC2 activity in numerous regions of the nervous system including the hypothalamus, hippocampus and spinal cord. We present key evidence from the literature suggesting that GPCR signalling is a conserved mechanism for regulating chloride homeostasis. This evidence includes: (1) the activation of group 1 metabotropic glutamate receptors and metabotropic Zn2+ receptors strengthens GABAergic inhibition in CA3 pyramidal neurons through a regulation of KCC2; (2) activation of the 5‐hydroxytryptamine type 2A serotonin receptors upregulates KCC2 cell surface expression and function, restores endogenous inhibition in motoneurons, and reduces spasticity in rats; and (3) activation of A3A‐type adenosine receptors rescues KCC2 dysfunction and reverses allodynia in a model of neuropathic pain. We propose that GPCR‐signals are novel endogenous Cl− extrusion enhancers that may regulate KCC2 function.

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Section: Discussionmentioning

confidence: 99%

Regulation of neuronal chloride homeostasis by neuromodulators

Mahadevan

Woodin

2016

The Journal of Physiology

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“…Structural models were generated using I-TASSER, MOE (http://www.chemcomp.com/) and Modeller 9v8 (48,49). The EBV B95-8 EBNA1 sequence was input to I-TASSER, which uses homology modelling where available and unaligned regions are modelled ab initio.…”

Section: Molecular Modellingmentioning

confidence: 99%

“…The structures were refined in terms of global topology (49). Models were generated in MOE using the template 1B3T (with and without DNA) and ad hoc outgap modelling to similar fragments from PDB for the remainder of the sequence, as follows.…”

Section: Molecular Modellingmentioning

confidence: 99%

Modelling the structure of full-length Epstein–Barr virus nuclear antigen 1

2014

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Abstract:Epstein-Barr virus (EBV) is a clinically important human virus associated with several cancers and is the etiologic agent of infectious mononucleosis. The viral nuclear antigen-1 (EBNA1) is central to the replication and propagation of the viral genome and likely contributes to tumourigenesis. We have compared EBNA1 homologues from other primate lymphocryptoviruses (LCV) and found that the central glycine/alanine repeat (GAr) domain, as well as predicted cellular protein (USP7 and CK2) binding sites are present in homologues in the Old World primates, but not the marmoset; suggesting that these motifs may have co-evolved. Using the resolved structure of the C-terminal one third of EBNA1 (homodimerisation and DNA binding domain), we have gone on to develop monomeric and dimeric models in silico of the full length protein.The C-terminal domain is predicted to be structurally highly similar between homologues, indicating conserved function. Zinc could be stably incorporated into the model, bonding with two N-terminal cysteines predicted to facilitate multimerisation. The GAr contains secondary structural elements in the models, while the protein binding regions are unstructured, irrespective of the prediction approach used and sequence origin. These intrinsically disordered regions may facilitate the diversity observed in partner interactions. We hypothsise that the structured GAr could mask the disordered regions, thereby protecting the protein from default degradation. In the dimer conformation, the C-terminal tails of each monomer wrap around a proline-rich protruding loop of the partner monomer, providing dimer stability, a feature which could be exploited in therapeutic design. Powered by Editorial Manager® and ProduXion Manager® from Aries Systems Corporation EBV-B95-8 hu-EBNA1CyEBV-TsBB6 cy-EBNA1 CeHV15 rh-EBNA1CeHV12 ba-EBNA1 CalHV3 ma EBNA1Modelling the structure of full length Epstein-Barr Virus Nuclear Antigen Figure S2. EBNA1 model comparison.The EBV B95-8 EBNA1 sequence was input to I-TASSER, which selected the EBNA1 C-terminal domain crystal structure (1B3T) and several fragment templates comprising: yeast fatty acid synthetase (2PFF), a-L-fucosidase (2Z8X), photosynthetic reaction centre (1C51), type A collagen (1YOF) and dimeric 6-phosphoglucouronate dehydrogenase (2ZYD). The 1B3T template was also used to generate models in MOE. EBNA1 models constructed using I-TASSER and MOE (and the composite of these two generated in Modeller9v8 (shown above), were assessed for structural plausibility using Molprobity and QMEAN score servers (table S1). Models were superimposed over the template (1B3T) and RMSD was estimated for each. The qualitative model energy analysis, normalised (QMEANnorm) score of a protein structural model provides a composite scoring function based on several geometrical aspects, both global (for the entire structure) and local (per residue), enabling the discrimination of good and bad models. The human and other primate LCV EBNA1 protein structure models (as indicated) were ...

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“…This approach is indirectly supported by the fact that in silico tools for building peptides (e.g., Pep-Fold [21] and I-Tasser [22]) are customarily used to build larger structures (i.e., with 9 or more amino acids). In this study we used the Protein Builder tool implemented in MOE (version 2012.10) [23] to build the peptides.…”

Section: Dataset Preparationmentioning

confidence: 99%

Prediction and interpretation of the lipophilicity of small peptides

Visconti

Ermondi

Esposito

2015

J Comput Aided Mol Des

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Peptide-based drug discovery has considerably expanded and solid in silico tools for the prediction of physico-chemical properties of peptides are urgently needed. In this work we tested some combinations of descriptors/algorithms to find the best model to predict log D oct of a series of peptides. To do that we evaluate the models statistical performances but also their skills in providing a reliable deconvolution of the balance of intermolecular forces governing the partitioning phenomenon. Results prove that a PLS model based on VolSurf+ descriptors is the best tool to predict log D oct of neutral and ionised peptides. The mechanistic interpretation also reveals that the inclusion in the chemical structure of a HBD group is more efficient in decreasing lipophilicity than the inclusion of a HBA group.

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I-TASSER: a unified platform for automated protein structure and function prediction

Cited by 5,777 publications

References 72 publications

Regulation of neuronal chloride homeostasis by neuromodulators

Regulation of neuronal chloride homeostasis by neuromodulators

Modelling the structure of full-length Epstein–Barr virus nuclear antigen 1

Prediction and interpretation of the lipophilicity of small peptides

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