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Relevant academic research and scientific papers

Disease-Causing Mutations in the G Protein Gαs Subvert the Roles of GDP and GTP

The single most frequent cancer-causing mutation across all heterotrimeric G proteins is R201C in Gαs. The current model explaining the gain-of-function activity of the R201 mutations is through the loss of GTPase activity and resulting inability to switch off to the GDP state. Here, we find that the R201C mutation can bypass the need for GTP binding by directly activating GDP-bound Gαs through stabilization of an intramolecular hydrogen bond network. Having found that a gain-of-function mutation can convert GDP into an activator, we postulated that a reciprocal mutation might disrupt the normal role of GTP. Indeed, we found R228C, a loss-of-function mutation in Gαs that causes pseudohypoparathyroidism type 1a (PHP-Ia), compromised the adenylyl cyclase-activating activity of Gαs bound to a non-hydrolyzable GTP analog. These findings show that disease-causing mutations in Gαs can subvert the canonical roles of GDP and GTP, providing new insights into the regulation mechanism of G proteins. Frequent pathogenic mutations in G proteins can cause signaling activation by converting GDP into an activator, rather than locking the proteins at a GTP-bound state.

Singlet vinylcarbenes: Spectroscopy and photochemistry

The first direct spectroscopic characterization of singlet vinylcarbenes is reported. Several vinyl amidines were converted to the corresponding vinylchlorodiazirines through straightforward Graham oxidation. Irradiation of the diazirines at 8 K in N2 matrices gave the corresponding singlet vinylchlorocarbenes, which could be characterized by IR, UV/vis, and calculational modeling. Hence, vinylchlorocarbene, 1-methylvinylchlorocarbene, and 1-cyclopentenylchlorocarbene were all generated and investigated. The spectra are consistent with localized carbene structures compared to the very delocalized triplet vinylcarbenes. In all cases, the carbenes readily cyclize to the corresponding cyclopropenes on visible irradiation, together with H-shift in the parent vinylchlorocarbene. In the cyclopentenyl system, cyclization leads to a highly strained bicyclo[3.1.0]hexene. Copyright

Site-specific and regiospecific installation of methylarginine analogues into recombinant histones and insights into effector protein binding

Arginine methylation has emerged as a widespread post-translational modification with influence over myriad cellular processes. However, the molecular mechanisms underlying such methylarginine-dependent phenomena remain unclear. To aid in this research, a facile method was developed to install methylarginine analogues on recombinant protein for use in biochemical, biophysical, and structural studies. Through chemical conjugation of novel α,β-unsaturated amidine precursors with proteins, methylarginine mimics can be displayed with control of methylation site, extent, and regiospecificity. Analogue installation into histones using this strategy produced modified proteins that were recognized by antibodies specific to endogenous methylarginine, and these histones retained the capacity to form mononucleosomes. Moreover, a native methylarginine-specific binding domain was shown to interact with methylarginine analogue-modified substrates. This chemical conjugation method for installing methylarginine analogues provides an efficient route to produce homogeneous modified proteins for subsequent investigations of methylarginine-dependent processes.

An efficient conversion of nitriles to amidines

A convenient method has been developed for direct conversion of nitriles to amidines in high yields. The method can also be applied to the preparation of guanidines from N-alkyl cyanamides.