CoDNaS: a database of conformational diversity in the native state of proteins

Monzón, Alexander Miguel; Juritz, Ezequiel; Fornasari, Marı́a Silvina; Parisi, Gustavo

doi:10.1093/bioinformatics/btt405

Cited by 31 publications

(31 citation statements)

References 24 publications

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“…Our set of active and inactive EGFR kinase structures has been selected from CoDNAS corresponding to the canonical sequence of the human EGFR (UniProtKB ID: P00533). EGFR kinase is a domain with N = 277 residues plus the activation loop.…”

Section: Methodsmentioning

confidence: 99%

Dynamics fingerprints of active conformers of epidermal growth factor receptor kinase

et al. 2018

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Epidermal growth factor receptor (EGFR) is a prototypical cellsurface receptor that plays a key role in the regulation of cellular signaling, proliferation and differentiation. Mutations of its kinase domain have been associated with the development of a variety of cancers and, therefore, it has been the target of drug design. Single amino acid substitutions (SASs) in this domain have been proven to alter the equilibrium of pre-existing conformer populations. Despite the advances in structural descriptions of its so-called active and inactive conformations, the associated dynamics aspects that characterize them have not been thoroughly studied yet. As the dynamic behaviors and molecular motions of proteins are important for a complete understanding of their structure-function relationships we present a novel procedure, using (or based on) normal mode analysis, to identify the collective dynamics shared among different conformers in EGFR kinase. The method allows the comparison of patterns of low-frequency vibrational modes defining representative directions of motions. Our procedure is able to emphasize the main similarities and differences between the collective dynamics of different conformers. In the case of EGFR kinase, two representative directions of motions have been found as dynamics fingerprints of the active conformers. Protein motion along both directions reveals to have a significant impact on the cavity volume of the main pocket of the active site. Otherwise, the inactive conformers exhibit a more heterogeneous distribution of collective motions.

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Section: Methodsmentioning

confidence: 99%

Dynamics fingerprints of active conformers of epidermal growth factor receptor kinase

et al. 2018

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“…Of the patients analyzed, 210 exhibited nonsynonymous sequence variants in the sequenced exons that were checked in COSMIC (Forbes et al, 2011), Humsavar (Humsavar Database, Geneva, Switzerland: Swiss Institute of Bioinformatics, http://www.uniprot.org/docs/humsavar), ClinVar (ClinVar database, Release weekly,Bethesda, MD, USA: National Center for Biotechnology Information, US, National Library of Medicine, (http://www.ncbi.nlm.nih.gov/clinvar/), DMDM (Peterson et al, 2010) and bibliographic databases to verify previous reports. To evaluate whether these variants involved structural and/or functionally relevant positions, the structures of different conformers were extracted from the CoDNas database (Monzon et al, 2013). These conformers were the inactive and active EGFR kinase domain forms, as monomers or dimers (respectively, Protein Data Bank codes: 4i20, 1m14, 2gs7 or 3gt8, and 4g5p).…”

Section: Methodsmentioning

confidence: 99%

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2015

Annals of Human Genetics

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SummarySomatic sequence variants in the epidermal growth factor receptor (EGFR) kinase domain are associated with sensitivity to tyrosine kinase inhibitors (TKIs) in patients with nonsmall cell lung cancer (NSCLC). Patients exhibiting sequence variants in this domain that produce kinase activity enhancement, are more likely to benefit from TKIs than patients with EGFR wild-type disease. Although most NSCLC EGFR-related alleles are concentrated in a few positions, established protocols recommend sequencing EGFR exons 18-21. In this study, 21 novel somatic variants belonging to such exons in adult Argentinean patients affected with NSCLC are reported. Of these, 18 were single amino acid substitutions (SASs), occurring alone or in combination with another genetic alteration (complex cases), one was a short deletion, one was a short deletion-short insertion combination, and one was a duplication. New variants and different combinations of previously reported variants were also found. Moreover, two of the reported SASs occurred in previously unreported positions of the EGFR kinase domain. In order to characterize the new sequence variants, physicochemical, sequence and conformational analyses were also performed. A better understanding of sequence variants in NSCLC may facilitate the most appropriate treatment choice for this complex disease.

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“…A wide range of structural differences among conformers can be observed by comparing structures of the same protein obtained under different crystallization conditions. These differences result from the relative movements of large domains, secondary and tertiary element rearrangements, and loop movements, which overall can produce a conformational diversity up to 4–5 Å of RMSD . Even up to 15–20 Å can be observed, depending on the structural alignment algorithm used to calculate the RMSD .…”

Section: Introductionmentioning

confidence: 99%

“…These differences result from the relative movements of large domains, 20 secondary and tertiary element rearrangements, 21 and loop movements, 22 which overall can produce a conformational diversity up to 4-5 Å of RMSD. [23][24][25][26] Even up to 15-20 Å can be observed, depending on the structural alignment algorithm used to calculate the RMSD. 18 Taking into account this extent of conformational diversity, performance of TBM methods should be re-evaluated.…”

Section: Introductionmentioning

confidence: 99%

Homology modeling in a dynamical world

et al. 2017

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A key concept in template-based modeling (TBM) is the high correlation between sequence and structural divergence, with the practical consequence that homologous proteins that are similar at the sequence level will also be similar at the structural level. However, conformational diversity of the native state will reduce the correlation between structural and sequence divergence, because structural variation can appear without sequence diversity. In this work, we explore the impact that conformational diversity has on the relationship between structural and sequence divergence. We find that the extent of conformational diversity can be as high as the maximum structural divergence among families. Also, as expected, conformational diversity impairs the well-established correlation between sequence and structural divergence, which is nosier than previously suggested. However, we found that this noise can be resolved using a priori information coming from the structure-function relationship. We show that protein families with low conformational diversity show a well-correlated relationship between sequence and structural divergence, which is severely reduced in proteins with larger conformational diversity. This lack of correlation could impair TBM results in highly dynamical proteins. Finally, we also find that the presence of order/disorder can provide useful beforehand information for better TBM performance.

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CoDNaS: a database of conformational diversity in the native state of proteins

Abstract: The database is freely available at http://www.codnas.com.ar/.

Cited by 31 publications

References 24 publications

Dynamics fingerprints of active conformers of epidermal growth factor receptor kinase

Dynamics fingerprints of active conformers of epidermal growth factor receptor kinase

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Homology modeling in a dynamical world

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