Abstract
Phosphoryl transfer reactions figure prominently in energy metabolism, signaling, transport and motility. Prior detailed studies of selected systems have highlighted mechanistic features that distinguish different phosphoryl transfer enzymes. Here, a top-down approach is developed for comparing statistically the active site configurations between populations of diverse structures in the Protein Data Bank, and it reveals patterns of hydrogen bonding that transcend enzyme families. Through analysis of large samples of structures, insights are drawn at a level of detail exceeding the experimental precision of an individual structure. In phosphagen kinases, for example, hydrogen bonds with the O3b of the nucleotide substrate are revealed as analogous to those in unrelated G proteins. In G proteins and other enzymes, interactions with O3b have been understood in terms of electrostatic favoring of the transition state. Ground state quantum mechanical calculations on model compounds show that the active site interactions highlighted in our database analysis can affect substrate phosphate charge and bond length, in ways that are consistent with prior experimental observations, by modulating hyperconjugative orbital interactions that weaken the scissile bond. Testing experimentally the inference about the importance of O3βinteractions in phosphagen kinases, mutation of arginine kinase Arg280decreases kcat, as predicted, with little impact upon KM.
| Original language | English (US) |
|---|---|
| Article number | e108310 |
| Journal | PLoS One |
| Volume | 9 |
| Issue number | 9 |
| DOIs | |
| State | Published - Sep 19 2014 |
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ASJC Scopus subject areas
- Agricultural and Biological Sciences(all)
- Biochemistry, Genetics and Molecular Biology(all)
- Medicine(all)
Cite this
Common hydrogen bond interactions in diverse phosphoryl transfer active sites. / Summerton, Jean C.; Martin, Gregory M.; Evanseck, Jeffrey D.; Chapman, Michael.
In: PLoS One, Vol. 9, No. 9, e108310, 19.09.2014.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Common hydrogen bond interactions in diverse phosphoryl transfer active sites
AU - Summerton, Jean C.
AU - Martin, Gregory M.
AU - Evanseck, Jeffrey D.
AU - Chapman, Michael
PY - 2014/9/19
Y1 - 2014/9/19
N2 - Phosphoryl transfer reactions figure prominently in energy metabolism, signaling, transport and motility. Prior detailed studies of selected systems have highlighted mechanistic features that distinguish different phosphoryl transfer enzymes. Here, a top-down approach is developed for comparing statistically the active site configurations between populations of diverse structures in the Protein Data Bank, and it reveals patterns of hydrogen bonding that transcend enzyme families. Through analysis of large samples of structures, insights are drawn at a level of detail exceeding the experimental precision of an individual structure. In phosphagen kinases, for example, hydrogen bonds with the O3b of the nucleotide substrate are revealed as analogous to those in unrelated G proteins. In G proteins and other enzymes, interactions with O3b have been understood in terms of electrostatic favoring of the transition state. Ground state quantum mechanical calculations on model compounds show that the active site interactions highlighted in our database analysis can affect substrate phosphate charge and bond length, in ways that are consistent with prior experimental observations, by modulating hyperconjugative orbital interactions that weaken the scissile bond. Testing experimentally the inference about the importance of O3βinteractions in phosphagen kinases, mutation of arginine kinase Arg280decreases kcat, as predicted, with little impact upon KM.
AB - Phosphoryl transfer reactions figure prominently in energy metabolism, signaling, transport and motility. Prior detailed studies of selected systems have highlighted mechanistic features that distinguish different phosphoryl transfer enzymes. Here, a top-down approach is developed for comparing statistically the active site configurations between populations of diverse structures in the Protein Data Bank, and it reveals patterns of hydrogen bonding that transcend enzyme families. Through analysis of large samples of structures, insights are drawn at a level of detail exceeding the experimental precision of an individual structure. In phosphagen kinases, for example, hydrogen bonds with the O3b of the nucleotide substrate are revealed as analogous to those in unrelated G proteins. In G proteins and other enzymes, interactions with O3b have been understood in terms of electrostatic favoring of the transition state. Ground state quantum mechanical calculations on model compounds show that the active site interactions highlighted in our database analysis can affect substrate phosphate charge and bond length, in ways that are consistent with prior experimental observations, by modulating hyperconjugative orbital interactions that weaken the scissile bond. Testing experimentally the inference about the importance of O3βinteractions in phosphagen kinases, mutation of arginine kinase Arg280decreases kcat, as predicted, with little impact upon KM.
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U2 - 10.1371/journal.pone.0108310
DO - 10.1371/journal.pone.0108310
M3 - Article
C2 - 25238155
AN - SCOPUS:84962343686
VL - 9
JO - PLoS One
JF - PLoS One
SN - 1932-6203
IS - 9
M1 - e108310
ER -