Search for allosteric disulfide bonds in NMR structures

Bryan Schmidt,Philip J Hogg

doi:10.1186/1472-6807-7-49

Abstract

BackgroundAllosteric disulfide bonds regulate protein function when they break and/or form. They typically have a -RHStaple configuration, which is defined by the sign of the five chi angles that make up the disulfide bond.ResultsAll disulfides in NMR and X-ray protein structures as well as in refined structure datasets were compared and contrasted for configuration and strain energy.ConclusionThe mean dihedral strain energy of 55,005 NMR structure disulfides was twice that of 42,690 X-ray structure disulfides. Moreover, the energies of all twenty types of disulfide bond was higher in NMR structures than X-ray structures, where there was an exponential decrease in the mean strain energy as the incidence of the disulfide type increased. Evaluation of protein structures for which there are X-ray and NMR models shows that the same disulfide bond can exist in different configurations in different models. A disulfide bond configuration that is rare in X-ray structures is the -LHStaple. In NMR structures, this disulfide is characterised by a particularly high potential energy and very short α-carbon distance. The HIV envelope glycoprotein gp120, for example, is regulated by thiol/disulfide exchange and contains allosteric -RHStaple bonds that can exist in the -LHStaple configuration. It is an open question which form of the disulfide is the functional configuration.

Highlights

Allosteric disulfide bonds regulate protein function when they break and/or form
42,690 were found in X-ray structures, 55,005 in the separate NMR structures, and 46 were from structures determined by the other methods
There is a mean of 1.4 disulfide bonds listed per X-ray structure file in the PDB. This is higher than the mean of 0.6 disulfide bonds per NMR structure and 0.9 disulfide bonds per structure determined by other methods

Summary

Introduction

Allosteric disulfide bonds regulate protein function when they break and/or form. They typically have a -RHStaple configuration, which is defined by the sign of the five chi angles that make up the disulfide bond. Considering that disulfide bonds will only form between optimally placed Cys in the tertiary structure, it follows that these bonds are a relatively recent addition to proteins. Most protein disulfide bonds are motifs that stabilise the tertiary and quaternary protein structure. These bonds are thought to assist protein folding by decreasing the entropy of the unfolded form [4]. There are two types of functional disulfides; the catalytic and allosteric bonds

Methods

Results

Conclusion