Native-state conformational dynamics of GART: a regulatory pH-dependent coil-helix transition examined by electrostatic calculations

Protein Science : a Publication of the Protein Society
D MorikisJ A McCammon

Abstract

Glycinamide ribonucleotide transformylase (GART) undergoes a pH-dependent coil-helix transition with pK(a) approximately 7. An alpha-helix is formed at high pH spanning 8 residues of a 21-residue-long loop, comprising the segment Thr120-His121-Arg122-Gln123-Ala124-Leu125-Glu126-Asn127. To understand the electrostatic nature of this loop-helix, called the activation loop-helix, which leads to the formation and stability of the alpha-helix, pK(a) values of all ionizable residues of GART have been calculated, using Poisson-Boltzmann electrostatic calculations and crystallographic data. Crystallographic structures of high and low pH E70A GART have been used in our analysis. Low pK(a) values of 5.3, 5.3, 3.9, 1.7, and 4.7 have been calculated for five functionally important histidines, His108, His119, His121, His132, and His137, respectively, using the high pH E70A GART structure. Ten theoretical single and double mutants of the high pH E70A structure have been constructed to identify pairwise interactions of ionizable residues, which have aided in elucidating the multiplicity of electrostatic interactions of the activation loop-helix, and the impact of the activation helix on the catalytic site. Based on our pK(a) calculations and ...Continue Reading

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Citations

Sep 23, 2003·Biophysical Chemistry·Dimitrios MorikisJ Andrew McCammon
Oct 18, 2001·Protein Science : a Publication of the Protein Society·D MorikisJ A McCammon
Aug 21, 2013·The Journal of Chemical Physics·Brian J NabloJohn J Kasianowicz
Jun 10, 2004·The Journal of Immunology : Official Journal of the American Association of Immunologists·Dimitrios Morikis, John D Lambris
Apr 13, 2011·Biotechnology Progress·Chris A KieslichDimitrios Gunopulos
Aug 6, 2021·The Journal of Physical Chemistry. B·Pancham Lal GuptaAdrian E Roitberg

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