conformational equilibrium
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2021 ◽  
Author(s):  
chang zhao ◽  
Wang-Jian Sheng ◽  
ying wang ◽  
Jie Zheng ◽  
Xiangqian Xie ◽  
...  

Abstract Lanthipeptides are an important group of natural products with diverse biological functions, and their biosynthesis requires the removal of N-terminal leader peptides (LPs) by designated proteases. LanPM1 enzymes, a subgroup of M1 zinc-metallopeptidases, are recently identified as bifunctional proteases with both endo- and aminopeptidase activities to remove LPs of class III and class IV lanthipeptides. Herein, we report the biochemical and structural characterization of EryP as the LanPM1 enzyme from the biosynthesis of class III lanthipeptide erythreapeptin. We determined X-ray crystal structures of EryP in three conformational states, the open, intermediate and closed states and identified a unique inter-domain Ca binding site as a regulatory element to modulate its domain dynamics and proteolytic activity. Inspired by the regulatory Ca binding, we develop a strategy to engineer LanPM1 enzymes for enhanced catalytic activities by strengthening inter-domain associations and driving the conformational equilibrium toward their closed forms.


2021 ◽  
Author(s):  
Akiko Asano ◽  
Maki Nakagawa ◽  
Chihiro Miyajima ◽  
Mami Yasui ◽  
Katsuhiko Minoura ◽  
...  

2021 ◽  
Vol 65 (3) ◽  
Author(s):  
Fatima M. Soto-Suárez ◽  
Víctor Duarte-Alaniz ◽  
Ramiro F. Quijano-Quiñones ◽  
Gabriel Cuevas

Abstract. The inversion process of 1,3-cyclohexanedione was studied to know the energy associated with the chair-chair interconversion. 1,3-cyclohexanedione has a conformational inversion energy of 1.87 kcal/mol evaluated at M06-2x/6-311++G(2d,2p) level of theory. The global process combines inversion and topomerization originated by boat-boat interconversion that includes only two trajectories to the inversion transition state but no six-like cyclohexane, or four-like oxane and thiane. The process includes two different twisted boats associated with a boat transition state. A global scheme is proposed to represent this conformational equilibrium.   Resumen. Se estudió el proceso de inversión de la 1,3-ciclohexanediona para conocer la energía asociada a la interconversión silla-silla. La 1,3-ciclohexanediona tiene una energía de inversión conformacional de 1.87 kcal/mol evaluada al nivel de teoría M06-2x/6-311++G(2d,2p). El proceso global combina la inversión y la topomerización originada por la interconversion entre dos confórmeros de bote, que incluye sólo dos trayectorias que conectan con el estado de transición de inversión, a diferencia del ciclohexano que tiene seis, y el oxano y el tiano que cuentan con cuatro. El proceso incluye dos estructuras de botes torcido diferentes asociados a un estado de transición de bote. Se propone un esquema global para representar este equilibrio conformacional.


Molecules ◽  
2021 ◽  
Vol 26 (11) ◽  
pp. 3109
Author(s):  
Łukasz Hetmańczyk ◽  
Przemysław Szklarz ◽  
Agnieszka Kwocz ◽  
Maria Wierzejewska ◽  
Magdalena Pagacz-Kostrzewa ◽  
...  

Conformational and polymorphic states in the nitro-derivative of o-hydroxy acetophenone have been studied by experimental and theoretical methods. The potential energy curves for the rotation of the nitro group and isomerization of the hydroxyl group have been calculated by density functional theory (DFT) to estimate the barriers of the conformational changes. Two polymorphic forms of the studied compound were obtained by the slow and fast evaporation of polar and non-polar solutions, respectively. Both of the polymorphs were investigated by Infrared-Red (IR) and Raman spectroscopy, Incoherent Inelastic Neutron Scattering (IINS), X-ray diffraction, nuclear quadrupole resonance spectroscopy (NQR), differential scanning calorimetry (DSC) and density functional theory (DFT) methods. In one of the polymorphs, the existence of a phase transition was shown. The position of the nitro group and its impact on the crystal cell of the studied compound were analyzed. The conformational equilibrium determined by the reorientation of the hydroxyl group was observed under argon matrix isolation. An analysis of vibrational spectra was achieved for the interpretation of conformational equilibrium. The infrared spectra were measured in a wide temperature range to reveal the spectral bands that were the most sensitive to the phase transition and conformational equilibrium. The results showed the interrelations between intramolecular processes and macroscopic phenomena in the studied compound.


2021 ◽  
Author(s):  
Ruidan Shen ◽  
Rory Crean ◽  
Sean Johnson ◽  
Shina Caroline Lynn Kamerlin ◽  
Alvan C. Hengge

<p>Catalysis by protein tyrosine phosphatases (PTPs) relies on the motion of a flexible protein loop (the WPD-loop) that carries a residue acting as a general acid/base catalyst during the PTP-catalyzed reaction. The orthogonal substitutions of a non-catalytic residue in the WPD-loops of YopH and PTP1B results in shifted pH-rate profiles, from an altered kinetic p<i>K</i><sub>a</sub> of the nucleophilic cysteine. Compared to WT, the G352T YopH variant has a broadened pH-rate profile, similar activity at optimal pH, but significantly higher activity at low pH. Changes in the corresponding PTP1B T177G variant are more modest and in the opposite direction, with a narrowed pH profile and less activity in the most acidic range. Crystal structures of the variants show no structural perturbations, but suggest an increased preference for the WPD-loop closed conformation. Computational analysis confirms a shift in loop conformational equilibrium in favor of the closed conformation, arising from a combination of increased stability of the closed state and destabilization of the loop-open state. Simulations identify the origins of this population shift, revealing differences in the flexibility of the WPD-loop and neighboring regions. Our results demonstrate that changes to the pH dependency of catalysis by PTPs can result from small changes in amino acid composition in their WPD-loops affecting only loop dynamics and conformational equilibrium. The perturbation of kinetic p<i>K</i><sub>a</sub> values of catalytic residues by non-chemical processes affords a means for nature to alter an enzyme’s pH dependency by a less disruptive path than altering electrostatic networks around catalytic residues themselves. </p>


2021 ◽  
Vol 81 (7) ◽  
pp. 1439-1452.e9
Author(s):  
Max E. Wilkinson ◽  
Sebastian M. Fica ◽  
Wojciech P. Galej ◽  
Kiyoshi Nagai

2021 ◽  
pp. mbc.E20-01-0089
Author(s):  
Radha Akella ◽  
John M. Humphreys ◽  
Kamil Sekulski ◽  
Haixia He ◽  
Mateusz Durbacz ◽  
...  

WNK kinases regulate electro-neutral cotransporters that are controlled by osmotic stress and chloride. We showed previously that autophosphorylation of WNK1 is inhibited by chloride, raising the possibility that WNKs are activated by osmotic stress. Here we demonstrate that unphosphorylated WNK isoforms 3 and 1 autophosphorylate in response to osmotic pressure in vitro, applied with the crowding agent polyethylene glycol 400 or osmolyte ethylene glycol, and that this activation is opposed by chloride. Small Angle X-ray Scattering of WNK3 in the presence and absence of PEG400, static light scattering in ethylene glycol, and crystallography of WNK1 were used to understand mechanism. Osmosensing in WNK3 and WNK1 appear to occur through a conformational equilibrium between an inactive, unphosphorylated, chloride-binding dimer and an autophosphorylation-competent monomer. An improved structure of the inactive kinase domain of WNK1, and a comparison with the structure of a monophosphorylated form of WNK1, suggests that large cavities, greater hydration, and specific bound water may participate in the osmosensing mechanism. Our prior work showed that osmolytes have effects on the structure of phosphorylated WNK1, suggestive of multiple stages of osmotic regulation in WNKs.


2021 ◽  
pp. 166878
Author(s):  
George R. Nahass ◽  
Yuanzi Sun ◽  
Yong Xu ◽  
Mark Batchelor ◽  
Madeleine Reilly ◽  
...  

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