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1. Methyl β-lactoside [methyl β- D -galactopyranosyl-(1→4)-β- D -glucopyranoside] monohydrate: a solvomorphism study

   https://doi.org/10.1107/S2053229621009499  

   Lin, Jieye; Oliver, Allen G.; Serianni, Anthony S. (October 2021, Acta Crystallographica Section C Structural Chemistry)

   Methyl β-lactoside [methyl β-D-galactopyranosyl-(1→4)-β-D-glucopyranoside] monohydrate, C 13 H 24 O 11 ·H 2 O, (I), was obtained via spontaneous transformation of methyl β-lactoside methanol solvate, (II), during air-drying. Cremer–Pople puckering parameters indicate that the β-D-Gal p (β-D-galactopyranosyl) and β-D-Glc p (β-D-glucopyranosyl) rings in (I) adopt slightly distorted 4 C 1 chair conformations, with the former distorted towards a boat form ( B C1,C4 ) and the latter towards a twist-boat form ( O5 S C2 ). Puckering parameters for (I) and (II) indicate that the conformation of the βGal p ring is slightly more affected than the βGlc p ring by the solvomorphism. Conformations of the terminal O -glycosidic linkages in (I) and (II) are virtually identical, whereas those of the internal O -glycosidic linkage show torsion-angle changes of 6° in both C—O bonds. The exocyclic hydroxymethyl group in the βGal p residue adopts a gt conformation (C4′ anti to O6′) in both (I) and (II), whereas that in the βGlc p residue adopts a gg ( gauche – gauche ) conformation (H5 anti to O6) in (II) and a gt ( gauche – trans ) conformation (C4 anti to O6) in (I). The latter conformational change is critical to the solvomorphism in that it allows water to participate in three hydrogen bonds in (I) as opposed to only two hydrogen bonds in (II), potentially producing a more energetically stable structure for (I) than for (II). Visual inspection of the crystalline lattice of (II) reveals channels in which methanol solvent resides and through which solvent might exchange during solvomorphism. These channels are less apparent in the crystalline lattice of (I). 

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2. Modulation of TRPV2 by endogenous and exogenous ligands: A computational study

   https://doi.org/10.1002/pro.4490  

   Feng, Shasha; Pumroy, Ruth A.; Protopopova, Anna D.; Moiseenkova‐Bell, Vera Y.; Im, Wonpil (December 2022, Protein Science)

   Abstract Transient receptor potential vanilloid (TRPV) channels play various important roles in human physiology. As membrane proteins, these channels are modulated by their endogenous lipid environment as the recent wealth of structural studies has revealed functional and structural lipid binding sites. Additionally, it has been shown that exogenous ligands can exchange with some of these lipids to alter channel gating. Here, we used molecular dynamics simulations to examine how one member of the TRPV family, TRPV2, interacts with endogenous lipids and the pharmacological modulator cannabidiol (CBD). By computationally reconstituting TRPV2 into a typical plasma membrane environment, which includes phospholipids, cholesterol, and phosphatidylinositol (PIP) in the inner leaflet, we showed that most of the interacting surface lipids are phospholipids without strong specificity for headgroup types. Intriguingly, we observed that the C‐terminal membrane proximal region of the channel binds preferentially to PIP lipids. We also modelled two structural lipids in the simulation: one in the vanilloid pocket and the other in the voltage sensor‐like domain (VSLD) pocket. The simulation shows that the VSLD lipid dampens the fluctuation of the VSLD residues, while the vanilloid lipid exhibits heterogeneity both in its binding pose and in its influence on protein dynamics. Addition of CBD to our simulation system led to an open selectivity filter and a structural rearrangement that includes a clockwise rotation of the ankyrin repeat domains, TRP helix, and VSLD. Together, these results reveal the interplay between endogenous lipids and an exogenous ligand and their effect on TRPV2 stability and channel gating. 

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3. Unraveling GPCRs Allosteric Modulation. Cannabinoid 1 Receptor as a Case Study

   https://doi.org/10.1002/prot.26762  

   Cruz, Alejandro; Warshel, Arieh (November 2024, Proteins: Structure, Function, and Bioinformatics)

   ABSTRACT G‐protein‐coupled receptors (GPCRs) constitute one of the most prominent families of integral membrane receptor proteins that mediate most transmembrane signaling processes. Malfunction of these signal transduction processes is one of the underlying causes of many human pathologies (Parkinson's, Huntington's, heart diseases, etc), provoking that GPCRs are the largest family of druggable proteins. However, these receptors have been targeted traditionally by orthosteric ligands, which usually causes side effects due to the simultaneous targeting of homologous receptor subtypes. Allosteric modulation offers a promising alternative approach to circumvent this problematic and, thus, comprehending its details is a most important task. Here we use the Cannabinoid type‐1 receptor (CB1R) in trying to shed light on this issue, focusing on positive allosteric modulation. This is done by using the protein‐dipole Langevin‐dipole (PDLD) within the linear response approximation (LRA) framework (PDLD/S‐2000) along with our coarse‐grained (CG) model of membrane proteins to evaluate the dissociation constants (K_Bs) and cooperativity factors (αs) for a diverse series of CB1R positive allosteric modulators belonging to the 2‐phenylindole structural class, considering CP55940 as an agonist. The agreement with the experimental data evinces that significantly populated allosteric modulator:CB1R and allosteric modulator:CP55940:CB1R complexes have been identified and characterized successfully. Analyzing them, it has been determined that CB1R positive allosteric modulation lies in an outwards displacement of transmembrane α helix (TM) 4 extracellular end and in the regulation of the range of motion of a compound TM7 movement for binary and ternary complexes, respectively. In this respect, we achieved a better comprehension of the molecular architecture of CB1R positive allosteric site, identifying Lys192^3.28and Gly194^3.30as key residues regarding electrostatic interactions inside this cavity, and to rationalize (at both structural and molecular level) the exhibited stereoselectivity in relation to positive allosteric modulation activity by considered CB1R allosteric modulators. Additionally, putative/postulated allosteric binding sites have been screened successfully, identifying the real CB1R positive allosteric site, and most structure–activity relationship (SAR) studies of CB1R 2‐phenylindole allosteric modulators have been rationalized. All these findings point out towards the predictive value of the methodology used in the current work, which can be applied to other biophysical systems of interest. The results presented in this study contribute significantly to understand GPCRs allosteric modulation and, hopefully, will encourage a more thorough exploration of the topic. 

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4. A comparative study of metatranscriptomic assessment methods to characterize Microcystis blooms

   https://doi.org/10.1002/lom3.10465  

   Pound, Helena L.; Gann, Eric R.; Wilhelm, Steven W. (December 2021, Limnology and Oceanography: Methods)
5. Modulation of cortical beta oscillations influences motor vigor: A rhythmic TMS‐EEG study

   https://doi.org/10.1002/hbm.26149  

   Uehara, Kazumasa; Fine, Justin M.; Santello, Marco (February 2023, Human Brain Mapping)

   Abstract Previous electro‐ or magnetoencephalography (Electro/Magneto EncephaloGraphic; E/MEG) studies using a correlative approach have shown that β (13–30 Hz) oscillations emerging in the primary motor cortex (M1) are implicated in regulating motor response vigor and associated with an anti‐kinetic role, that is, slowness of movement. However, the functional role of M1 β oscillations in regulation of motor responses remains unclear. To address this gap, we combined EEG with rhythmic TMS (rhTMS) delivered to M1 at the β (20 Hz) frequency shortly before subjects performed an isometric ramp‐and‐hold finger force production task at three force levels. rhTMS is a novel approach that can modulate rhythmic patterns of neural activity. β‐rhTMS over M1 induced a modulation of neural oscillations to β frequency in the sensorimotor area and reduced peak force rate during the ramp‐up period relative to sham and catch trials. Interestingly, this rhTMS effect occurred only in the large force production condition. To distinguish whether the effects of rhTMS on EEG and behavior stemmed from phase‐resetting by each magnetic pulse or neural entrainment by the periodicity of rhTMS, we performed a control experiment using arrhythmic TMS (arTMS). arTMS did not induce changes in EEG oscillations nor peak force rate during the rump‐up period. Our results provide novel evidence that β neural oscillations emerging the sensorimotor area influence the regulation of motor response vigor. Furthermore, our findings further demonstrate that rhTMS is a promising tool for tuning neural oscillations to the target frequency. 

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