The Proapoptotic G41S Mutation to Human Cytochrome c Alters the Heme Electronic Structure and Increases the Electron Self-Exchange Rate.
Liptak, M.D., Fagerlund, R.D., Ledgerwood, E.C., Wilbanks, S.M., Bren, K.L.(2011) J Am Chem Soc 133: 1153-1155
- PubMed: 21192676 
- DOI: https://doi.org/10.1021/ja106328k
- Primary Citation of Related Structures:  
3NWV - PubMed Abstract: 
The naturally occurring G41S mutation to human (Hs) cytochrome (cyt) c enhances apoptotic activity based upon previous in vitro and in vivo studies, but the molecular mechanism underlying this enhancement remains unknown. Here, X-ray crystallography, nuclear magnetic resonance (NMR) spectroscopy, and density functional theory (DFT) calculations have been used to identify the structural and electronic differences between wild-type (WT) and G41S Hs cyt c. S41 is part of the hydrogen bonding network for propionate 7 of heme pyrrole ring A in the X-ray structure of G41S Hs cyt c and, compared to WT, G41S Hs cyt c has increased spin density on pyrrole ring C and a faster electron self-exchange rate. DFT calculations illustrate an electronic mechanism where structural changes near ring A can result in electronic changes at ring C. Since ring C is part of the solvent-exposed protein surface, we propose that this heme electronic structure change may ultimately be responsible for the enhanced proapoptotic activity of G41S Hs cyt c.
Organizational Affiliation: 
Department of Chemistry, University of Rochester, Rochester, New York 14627, United States.