How the Local Environment of Functional Sites Regulates Protein Function

Abstract

Proteins form complex biological machineries whose functions in the cell are highly regulated at both the cellular and molecular levels. Cellular regulation of protein functions involves differential gene expressions, post-translation modifications, and signaling cascades. Molecular regulation, on the other hand, involves tuning an optimal local protein environment for the functional site. Precisely how a protein achieves such an optimal environment around a given functional site is not well understood. Herein, by surveying the literature, we first summarize the various reported strategies used by certain proteins to ensure their correct functioning. We then formulate three key physicochemical factors for regulating a protein’s functional site, namely, (i) its immediate interactions, (ii) its solvent accessibility, and (iii) its conformational flexibility. We illustrate how these factors are applied to regulate the functions of free/metal-bound Cys and Zn sites in proteins.

Insights into the Role of the Discontinuous TM7 Helix of Human Ferroportin through the Prism of the Asp325 Residue

“…This salt-bridge holding the N-and C-lobes together may be linked to the presence of a metal ion in the C-lobe site, as it could not be formed in a metal-free OF state where the Asp325 rotamer is hydrogen-bonded to Cys326 (Figure 4C). In this case, Asp325 is likely to play a critical role in tuning an optimal local environment around Cys326, the SH group of which donates hydrogen bonds to the Asp325 carboxylate, while Asp325 is likely to allow Cys326 sulfur valence electrons to be polarized optimally for metal binding [26,27]. It thus seems likely that the negatively charged Asp325, which interacts only indirectly with Co 2+ (in contrast to Cys326 and His507), plays an important role in repositioning TM7b on substrate binding.…”

Into the Fray! A Beginner's Guide to Medicinal Chemistry

“…[151] suppressing oxidation by replacing or removing the alkoxy groups, replacing the biaryl system with electron-deficient heterocycles, as well as introducing additional electron-withdrawing halogens. [162] A subset of this library (110)(111)(112)(113)(114) maintained activity comparable to compound 109 with good activity against the human orthologue of SSTR5, but diminished activity against the mouse equivalent. Unsurprisingly, the lower activity against the mouse variant resulted in poorer in vivo activity in their mouse model.…”

“…This phenomenon is referred to as functional selectivity. [113,114] The factors which govern this effect are subtle, with some compounds possessing the ability to simultaneously act as either agonists, antagonists and inverse agonists at the same receptor. [103] Therefore, the ability to modulate what structural features of a compound may influence receptor response provides the opportunity to develop functional selectivity or signal bias and is therefore, an important tool in the development of selectivity.…”

Analysis of electrostatic coupling throughout the laboratory evolution of a designed retroaldolase

“…Very recently, Mazmanian, Sargsyan and Lim 3 reviewed how the environment of enzyme active sites, namely local interactions, the presence of solvent molecules, and conformational flexibility, control enzymatic function. Here we focus on the role of local interactions 4 , 5 between catalytic residues and nearby residues on the activity of a series of designed retroaldolases of the RA95 family, which has been optimized by laboratory evolution.…”