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Human isoforms conformational dynamics Conformations averaged over 2 replicates of 50-ns MD simulations exon g no f/g d f/g e i I j 1.0 0.5 0.0 10 210 215 220 5 Residue numbers w. f w. g wt. f/g 0 RMSF (A) n p 2.0 c 1.5 b 15 a RMSF (A) 20 2.5 3.0 exon f 0 100 200 Residue numbers 300 225 Human isoforms conformational dynamics exon f exon g F-helix G-helix no f/g MAP kinase insert The removal of the helices F, G and the “MAP kinase insert” (helices α1L14 and α2L14) allows for large amplitude motions of the A-loop. Structural and functional role of exon f/g exon f Stabilizing F-helix Exon f : D L W S V G C I M G E M V C H K I L F P G R D Exon g : D I W S V G C I M G E M I K G G V L F P G T D Anchor points for R- and C-spines 2.5 3.0 R228 K222 1.5 1.0 0.5 0.0 RMSF (A) 2.0 exon g 210 215 220 Residue numbers 225 Residues predicted as interacting by JET2 Protein binding site prediction exon f exon g no f/g For questions • X-ray structures? Yes more than 20, with interacting peptides or with inhibitors. 2 isoforms crystalized, one with exon f, one with exon g; essentially no change between them • What transcripts in Ensembl? Red or gold transcripts (protein coding). Gold transcripts and those with a CCDS (Consensus Coding Sequence Set) have coding sequences that are well-supported and are unlikely to change. Gold transcripts are identical between manual curation from the VEGA/Havana set project and the Ensembl automatic annotation pipeline. They are only available for human, mouse, and zebrafish. http://www.ensembl.org/Help/View?id=143 For questions • Quality of the models Normalized DOPE score (Z-score): The DOPE score is an atomic distance-dependent statistical potential based on a physical reference state that accounts for the finite size and spherical shape of proteins by assuming a protein chain consists of noninteracting atoms in a uniform sphere of radius equivalent to that of the corresponding protein. The normalized version (N-DOPE) was used instead of the raw score; it is a standard score (Z-score) derived from the statistics of raw DOPE scores. The mean and standard deviation of the DOPE score of a given protein is estimated from its sequence. The mean score of a random protein conformation is estimated by a weighted sum of protein composition over the 20 standard amino acid residue types, where each weight corresponds to the expected change in the score by inserting a specific type of amino acid residue. The weights are estimated from a separate training set of 1,686,320 models generated by MODPIPE. Eramian et al Protein Sci. 2008 Nov;17(11):1881-93. G-factors from PROCHECK: The G-factor provides a measure of how "normal", or alternatively how "unusual", a given stereochemical property is. In PROCHECK it is computed for properties reflecting the torsion angles and the covalent geometry. The G-factor is essentially just a logodds score based on the observed distributions of these stereochemical parameters. When applied to a given residue, a low G-factor indicates that the property corresponds to a lowprobability conformation. Engh RA and Huber R (1991). Accurate bond and angle parameters for X-ray protein structure refinement. Acta Cryst., A47, 392-400.