Computational analysis of the active sites in binary and ternary complexes of the vitamin D receptor

Sicińska, Wanda; Rotkiewicz, Piotr

doi:10.1016/j.jsbmb.2006.12.077

Cited by 2 publications

(5 citation statements)

References 7 publications

(7 reference statements)

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“…We however adopted the hAng (1ANG) as a reference to number all sites because the remaining human structures are highly similar in sequence and structure to this one. To identify differences among the six copies of mouse Angiogenin proteins' structures we used the program CCOMP, which measures the distance between the mass centres of amino acids of two structures by the Root Mean Square Deviation [53]. Although we observed no important differences in the structure among the Ang copies (for example, all six copies present less than 2Å root mean square deviations from the first copy; Table 3), our results point to the possible blockage of the active site in mAng2, which may explain the lack of mAng1-like activity (Figure 4).…”

Section: Resultsmentioning

confidence: 99%

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Mutational dynamics of murine angiogenin duplicates

2010

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BackgroundAngiogenin (Ang) is a protein involved in angiogenesis by inducing the formation of blood vessels. The biomedical importance of this protein has come from findings linking mutations in Ang to cancer progression and neurodegenerative diseases. These findings highlight the evolutionary constrain on Ang amino acid sequence. However, previous studies comparing human Angiogenin with homologs from other phylogenetically related organisms have led to the conclusion that Ang presents a striking variability. Whether this variability has an adaptive value per se remains elusive. Understanding why many functional Ang paralogs have been preserved in mouse and rat and identifying functional divergence mutations at these copies may explain the relationship between mutations and function. In spite of the importance of testing this hypothesis from the evolutionarily and biomedical perspectives, this remains yet unaccomplished. Here we test the main mutational dynamics driving the evolution and function of Ang paralogs in mammals.ResultsWe analysed the phylogenetic asymmetries between the different Ang gene copies in mouse and rat in the context of vertebrate Ang phylogeny. This analysis shows strong evidence in support of accelerated evolution in some Ang murine copies (mAng). This acceleration is not due to non-functionalisation because constraints on amino acid replacements remain strong. We identify many of the amino acid sites involved in signal localization and nucleotide binding by Ang to have evolved under diversifying selection. Compensatory effects of many of the mutations at these paralogs and their key structural location in or nearby important functional regions support a possible functional shift (functional divergence) in many Ang copies. Similarities between 3D-structural models for mAng copies suggest that their divergence is mainly functional.ConclusionsWe identify the main evolutionary dynamics shaping the variability of Angiogenin in vertebrates and highlight the plasticity of this protein after gene duplication. Our results suggest functional divergence among mAng paralogs. This puts forward mAng as a good system candidate for testing functional plasticity of such an important protein while stresses caution when using mouse as a model to infer the consequences of mutations in the single Ang copy of humans.

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Section: Resultsmentioning

confidence: 99%

“…To identify differences among the six copies of mouse Angiogenin proteins' structures we used the program CCOMP [53], that measures the Mean Root Square Deviation between the different structures.…”

Section: Methodsmentioning

confidence: 99%

Mutational dynamics of murine angiogenin duplicates

2010

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“…The preliminary version 3.30 of CCOMP program [12,14] http://www.pirx.com/ccomp calculated just coordinate root mean square deviation for all atoms of the individual amino acids. The amino acids with their RMSD exceeding the average value by 30%, or more, were subjected to further analysis.…”

Section: Computational Approachesmentioning

confidence: 99%

“…The fact that 20-epi-1␣,25-(OH) 2 D 3 , 1␣,25-(OH) 2 D 3 and Gemini with the "normal" branch of its side chain occupy the same part of VDR binding cavity, yet these compounds differ drastically in their biological activities, points on necessity of looking for differences between protein complexes on the level of atomic not residue length scale. Small alteration in VDR structure, like rotation of amino acid's side chains in response to the ligands might result in a conformation that preferentially accomodates co-activators responsible for selected biological potency [12].…”

Section: Introductionmentioning

confidence: 99%

“…Recently we described a preliminary version 3.30 of the Complex COMParison (CCOMP) program [12], which aided the comparison process by calculating values of the local RMSD between ␣-carbon coordinates of amino acids in two protein complexes. The purpose of this work is to identify subtle changes in the side chains of VDR residues caused by the presence of 20-epi compound.…”

Section: Introductionmentioning

confidence: 99%

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