Cl–π interactions in protein–ligand complexes Imai, Yumi N.; Inoue, Yoshihisa; Nakanishi, Isao ...
Protein science,
July 2008, 2008-Jul, 2008-07-00, 20080701, Letnik:
17, Številka:
7
Journal Article
Recenzirano
Odprti dostop
During systematic analysis of nonbonded contacts in protein–ligand complexes derived from crystal structures in the Protein Data Bank, Cl–π interactions have been found, not only in the ...well‐documented serine proteases but also, to a lesser extent, in other proteins. From geometric analysis of such Cl–π interactions in the crystal structures, two distinct geometries were found: the “edge‐on” approach of a Cl atom to a ring atom or C–C bond and the “face‐on” approach toward the ring centroid with an average interatomic distance of 3.6 Å. High‐level ab initio calculations using benzene–chlorohydrocarbon model systems elucidated that the calculated Cl–π interaction energy is −2.01 kcal/mol, and the dispersion force is the major source of attraction. We also discussed the geometric flexibility in Cl–π interactions and a relationship between the intensity of the π density in an aromatic ring and the interaction position of the Cl atom.
We sought to clarify a pathway by which L- and dD-arginine simulate insulin secretion in mice and cell lines and obtained the following novel two findings. (1) Using affinity magnetic nanobeads ...technology, we identified that proinsulin is retained in the endoplasmic reticulum (ER) through UDP-glucose:glycoprotein glucosyltransferase 1 (UGGT1) when arginine availability is limited. (2) L- and d-arginine release proinsulin from UGGT1 through competition with proinsulin and promote exit of proinsulin from the ER to Golgi apparatus. The ability of arginine to release proinsulin from UGGT1 closely correlates with arginine-induced insulin secretion in several models of β cells indicating that UGGT1-proinsulin interaction regulates arginine-induced insulin secretion.
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•UGGT1 binds to proinsulin in the absence of arginine.•Arginine competes with proinsulin and binds to UGGT1 in the ER.•Released proinsulin moves to Golgi apparatus and secretory vesicles to secrete.
The loss of functional β cell mass contributes to development and progression of type 2 diabetes (T2D). However, the molecular mechanisms differentiating islet dysfunction in T2D from nondiabetic ...states remain elusive. In this issue of the JCI, Son et al. applied reverse engineering to obtain the activity of gene expression regulatory proteins from single-cell RNA sequencing data of nondiabetic and T2D human islets. The authors identify unique patterns of regulatory protein activities associated with T2D. Furthermore, BACH2 emerged as a potential transcription factor that drives activation of T2D-associated regulatory proteins in human islets.
The loss of functional β cell mass contributes to development and progression of type 2 diabetes (T2D). However, the molecular mechanisms differentiating islet dysfunction in T2D from nondiabetic ...states remain elusive. In this issue of the JCI, Son et al. applied reverse engineering to obtain the activity of gene expression regulatory proteins from single-cell RNA sequencing data of nondiabetic and T2D human islets. The authors identify unique patterns of regulatory protein activities associated with T2D. Furthermore, BACH2 emerged as a potential transcription factor that drives activation of T2D-associated regulatory proteins in human islets.
In Japan, the percentage of physicians holding a PhD degree is high. Japanese MDs pursue a PhD after completing residency training and before moving on to clinical practice for the rest of their ...career. In Japan, most individuals with MD and PhD degrees received PhD training without much opportunity to continue research, with the exception of a few who were chosen by their professors to remain in academia. This system is very different from that in the US, where students have the option to enroll in combined MD/PhD programs that foster opportunities for physicians to pursue a research career at a very early stage. The US system also supports the continued development of physician-scientists into independent researchers through postgraduate training for individuals with DO, MD, and MD/PhD degrees. Here, Imai shares her experience as a physician-scientist in the US.
The fluoroquinolone antibiotic binding site in the hERG potassium channel was examined for the residues involved and their position in the tetrameric channel. The blocking effect of the two ...fluoroquinolones levofloxacin and sparfloxacin to tandem dimers of the hERG mutants were evaluated electrophysiologically. The results indicated that two Tyr652s in the neighboring subunits and one or two Phe656s in the diagonal subunits contributed to the blockade in the case of both compounds, and Ser624 was also involved. The docking studies suggested that the protonated carboxyl group in the compounds strongly interacts with Phe656 as a π acceptor.
We sought to determine a mechanism by which L-arginine increases glucose-stimulated insulin secretion (GSIS) in β-cells by finding a protein with affinity to L-arginine using arginine-immobilized ...magnetic nanobeads technology. Glucokinase (GCK), the key regulator of GSIS and a disease-causing gene of maturity-onset diabetes of the young type 2 (MODY2), was found to bind L-arginine. L-Arginine stimulated production of glucose-6-phosphate (G6P) and induced insulin secretion. We analyzed glucokinase mutants and identified three glutamate residues that mediate binding to L-arginine. One MODY2 patient with GCK
demonstrated lower C-peptide-to-glucose ratio after arginine administration. In β-cell line, GCK
reduced L-arginine-induced insulin secretion compared with GCK
. In addition, we elucidated that the binding of arginine protects glucokinase from degradation by E3 ubiquitin ligase cereblon mediated ubiquitination. We conclude that L-arginine induces insulin secretion by increasing G6P production by glucokinase through direct stimulation and by prevention of degradation.
To characterize drug binding to the human ether-à-go-go related gene (hERG) channel, a synergic approach interplaying patch-clamp experiments and a docking study was developed. Mutations were ...introduced into concatenated dimers of the hERG channel that were assembled into a heterotetramer with mutated diagonal subunits. The binding affinities of three drugs (cisapride, terfenadine, and N-4-1-2-(6-methyl-2-pyridinyl)ethyl-4-piperidinylcarbonylphenylmethanesulfonamide dihydrochloride (E-4031, 1)) to a set of mutant channels were examined electrophysiologically to assess the involved residues, their number, and relative positions. Cisapride and 1 interacted with Tyr652 residues on adjacent subunits, while terfenadine interacted with Tyr652 residues on diagonal, but not on adjacent, subunits. Phe656 was involved in the binding of all three drugs, and Ser624 was found to be only involved in cisapride and 1. The docking models demonstrated that π−π and CH−π interactions rather than cation−π interaction play a key role in drug binding to the hERG channel.
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