scholarly journals Which Properties Allow Ligands to Open and Bind to the Transient Binding Pocket of Human Aldose Reductase?

Biomolecules ◽  
2021 ◽  
Vol 11 (12) ◽  
pp. 1837
Author(s):  
Anna Sandner ◽  
Khang Ngo ◽  
Christoph P. Sager ◽  
Frithjof Scheer ◽  
Michael Daude ◽  
...  
Keyword(s):  
Crystal Structures ◽  
Charge Distribution ◽  
Aldose Reductase ◽  
Binding Pocket ◽  
Crystallographic Data ◽  
X Ray ◽  
X Ray Crystallography ◽  
Ph Values ◽  
Selective Ligands ◽  
Binding Position

The transient specificity pocket of aldose reductase only opens in response to specific ligands. This pocket may offer an advantage for the development of novel, more selective ligands for proteins with similar topology that lack such an adaptive pocket. Our aim was to elucidate which properties allow an inhibitor to bind in the specificity pocket. A series of inhibitors that share the same parent scaffold but differ in their attached aromatic substituents were screened using ITC and X-ray crystallography for their ability to occupy the pocket. Additionally, we investigated the electrostatic potentials and charge distribution across the attached terminal aromatic groups with respect to their potential to bind to the transient pocket of the enzyme using ESP calculations. These methods allowed us to confirm the previously established hypothesis that an electron-deficient aromatic group is an important prerequisite for opening and occupying the specificity pocket. We also demonstrated from our crystal structures that a pH shift between 5 and 8 does not affect the binding position of the ligand in the specificity pocket. This allows for a comparison between thermodynamic and crystallographic data collected at different pH values.

scholarly journals UHR PX and NPC studies of H-FABP water network with tiny perdeuterated crystals

2014 ◽  
Vol 70 (a1) ◽  
pp. C1200-C1200
Author(s):  
Alberto Podjarny ◽  
Matthew Blakeley ◽  
Michael Haertlein ◽  
Andre Mitschler ◽  
Alexandra Cousido-Siah ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Charge Distribution ◽  
Binding Pocket ◽  
Internal Cavity ◽  
Water Molecules ◽  
Fatty Acid Binding ◽  
X Ray ◽  
X Ray Crystallography ◽  
Internal Water ◽  
Dynamics Simulations

We have obtained very detailed information about the internal water molecules in the large internal cavity inside fatty acid binding (FABP) proteins , in the presence of bound fatty acids (FA), by Ultra High Resolution X-Ray Crystallography (UHR) to 0.7 Å and Neutron Protein Crystallography (NPC) to 1.9 Å using a "radically small" (V=0.05 mm3) crystal. These waters form a very well ordered dense cluster of 12 molecules, positioned between the hydrophilic internal wall of the cavity and the fatty acid molecule. This information has been used for a detailed electrostatic analysis based on the charge distribution description modeled in the multipole formalism and on the Atoms in Molecules theory. This information is also being used in molecular dynamics simulations of H-FABP and its complex with FA in order to quantify the energetic contribution of these internal waters to the binding energy. The experiment has been done with oleic acid, coming with the protein expressed in E. Coli. The results have been analyzed in order to understand the interactions between the FA, the internal water and the protein, and in particular the role played by the water molecules in determining the potency and specificity of FA binding to FABPs. The major tool for visualizing the water molecules inside the H-FABP cavity is UHR X-Ray Crystallography combined with NPC. UHR crystallographic structures give the positions of hydrogen and oxygen atoms for well-ordered water molecules. NPC determines hydrogen atom positions, particularly of water molecules which have multiple conformations, leading to the best possible crystallographic model. This model was then complemented by a transferred charge distribution to accurately determine the electrostatic and topological properties in the binding pocket, providing a description of the way water molecules in hydration layer contribute to the binding of ligand, which is essential to understand and model ligand binding.

Holographic methods in X-ray crystallography. III. First numerical results

1993 ◽  
Vol 49 (6) ◽  
pp. 866-871 ◽  
Author(s):  
G. J. Maalouf ◽  
J. C. Hoch ◽  
A. S. Stern ◽  
H. Szöke ◽  
A. Szöke
Keyword(s):  
Experimental Data ◽  
Crystal Structures ◽  
Numerical Experiments ◽  
Numerical Results ◽  
Crystallographic Data ◽  
Viable Alternative ◽  
Holographic Method ◽  
Acta Cryst ◽  
X Ray ◽  
X Ray Crystallography

The holographic method for the completion of crystal structures, described in paper II [Szöke (1993). Acta Cryst. A49, 853–866], is implemented numerically. The purpose of these modest calculations is to show that the holographic method can handle real crystallographic data in easy problems and to test various algorithms for its implementation. Both synthetic and experimental data are used and sources of error are systematically introduced. The numerical experiments support the theory presented in paper II and show that the holographic method may be a potentially viable alternative to conventional methods for the completion of crystal structures.

scholarly journals A mixed chirality α-helix in a stapled bicyclic and a linear antimicrobial peptide revealed by X-ray crystallography

2021 ◽  
Author(s):  
Stéphane Baeriswyl ◽  
Hippolyte Personne ◽  
Ivan Di Bonaventura ◽  
Thilo Köhler ◽  
Christian van Delden ◽  
...  
Keyword(s):  
Antimicrobial Peptides ◽  
Antimicrobial Peptide ◽  
Crystal Structures ◽  
X Ray ◽  
X Ray Crystallography ◽  
Α Helix

We report the first X-ray crystal structures of mixed chirality α-helices comprising only natural residues as the example of bicyclic and linear membrane disruptive amphiphilic antimicrobial peptides containing seven l- and four d-residues.

scholarly journals X-ray crystallography reveals molecular recognition mechanism for sugar binding in a melibiose transporter MelB

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Lan Guan ◽  
Parameswaran Hariharan
Keyword(s):  
Molecular Recognition ◽  
Binding Pocket ◽  
Cation Binding ◽  
Recognition Mechanism ◽  
X Ray ◽  
X Ray Crystallography ◽  
Sugar Binding ◽  
Sugar Specificity ◽  
Major Facilitator ◽  
Mfs Transporters

AbstractMajor facilitator superfamily_2 transporters are widely found from bacteria to mammals. The melibiose transporter MelB, which catalyzes melibiose symport with either Na+, Li+, or H+, is a prototype of the Na+-coupled MFS transporters, but its sugar recognition mechanism has been a long-unsolved puzzle. Two high-resolution X-ray crystal structures of a Salmonella typhimurium MelB mutant with a bound ligand, either nitrophenyl-α-d-galactoside or dodecyl-β-d-melibioside, were refined to a resolution of 3.05 or 3.15 Å, respectively. In the substrate-binding site, the interaction of both galactosyl moieties on the two ligands with MelBSt are virturally same, so the sugar specificity determinant pocket can be recognized, and hence the molecular recognition mechanism for sugar binding in MelB has been deciphered. The conserved cation-binding pocket is also proposed, which directly connects to the sugar specificity pocket. These key structural findings have laid a solid foundation for our understanding of the cooperative binding and symport mechanisms in Na+-coupled MFS transporters, including eukaryotic transporters such as MFSD2A.

Bis(1-phenyl-1-propyne) complexes of tungsten(II): crystal structures of [WI2(CO)(NCR)(η2-MeC2Ph)2] (R = Me, Et, or Ph)

2001 ◽  
Vol 79 (3) ◽  
pp. 263-271
Author(s):  
Paul K Baker ◽  
Michael GB Drew ◽  
Deborah S Evans
Keyword(s):  
Carbon Monoxide ◽  
Solid State ◽  
Crystal Structures ◽  
Octahedral Geometry ◽  
X Ray ◽  
X Ray Crystallography ◽  
Alkyne Complexes ◽  
First Time

Reaction of [WI2(CO)3(NCMe)2] with two equivalents of 1-phenyl-1-propyne (MeC2Ph) in CH2Cl2, and in the absence of light, gave the bis(1-phenyl-1-propyne) complex [WI2(CO)(NCMe)(η2-MeC2Ph)2] (1) in 77% yield. Treatment of equimolar quantities of 1 and NCR (R = Et, i-Pr, t-Bu, Ph) in CH2Cl2 afforded the nitrile-exchanged products, [WI2(CO)(NCR)(η2-MeC2Ph)2] (2-5) (R = Et (2), i-Pr (3), t-Bu (4), Ph (5)). Complexes 1, 2, and 5 were structurally characterized by X-ray crystallography. All three structures have the same pseudo-octahedral geometry, with the equatorial sites being occupied by cis and parallel alkyne groups, which are trans to the cis-iodo groups. The trans carbon monoxide and acetonitrile ligands occupy the axial sites. In structures 1 and 2, the methyl and phenyl substituents of the 1-phenyl-1-propyne ligands are cis to each other, whereas for the bulkier NCPh complex (5), the methyl and phenyl groups are trans to one another. This is the first time that this arrangement has been observed in the solid state in bis(alkyne) complexes of this type.Key words: bis(1-phenyl-1-propyne), carbonyl, nitrile, diiodo, tungsten(II), crystal structures.

Preparation and structural analysis of (±)-threo-ritalinic acid

2013 ◽  
Vol 69 (11) ◽  
pp. 1225-1228 ◽  
Author(s):  
Sara Wyss ◽  
Irmgard A. Werner ◽  
W. Bernd Schweizer ◽  
Simon M. Ametamey ◽  
Selena Milicevic Sephton
Keyword(s):  
Methyl Ester ◽  
Free Acid ◽  
Nmr Analysis ◽  
Intermolecular Hydrogen Bonds ◽  
X Ray ◽  
X Ray Crystallography ◽  
Ph Values ◽  
Ritalinic Acid ◽  
Methyl Phenidate ◽  
Hydrolysis Of

Hydrolysis of the methyl ester (±)-threo-methyl phenidate afforded the free acid in 40% yield,viz.(±)-threo-ritalinic acid, C13H17NO2. Hydrolysis and subsequent crystallization were accomplished at pH values between 5 and 7 to yield colourless prisms which were analysed by X-ray crystallography. Crystals of (±)-threo-ritalinic acid belong to theP21/nspace group and form intermolecular hydrogen bonds. An antiperiplanar disposition of the H atoms of the (HOOC—)CH—CHpygroup (py is pyridine) was found in both the solid (diffraction analysis) and solution state (NMR analysis). It was also determined that (±)-threo-ritalinic acid conforms to the minimization of negativegauche+–gauche−interactions.

The crystal structures of solvent-free alkali-metal squarates from powder diffraction data

2005 ◽  
Vol 220 (11) ◽  
Author(s):  
Robert E. Dinnebier ◽  
Hanne Nuss ◽  
Martin Jansen
Keyword(s):  
High Resolution ◽  
Alkali Metal ◽  
Crystal Structures ◽  
Powder Diffraction ◽  
Diffraction Data ◽  
Room Temperature ◽  
Solvent Free ◽  
Crystallographic Data ◽  
Powder Diffraction Data ◽  
X Ray

AbstractThe crystal structures of solvent-free lithium, sodium, rubidium, and cesium squarates have been determined from high resolution synchrotron and X-ray laboratory powder patterns. Crystallographic data at room temperature of Li

Crystallographic characterization of three cathinone hydrochlorides new on the NPS market: 1-(4-methylphenyl)-2-(pyrrolidin-1-yl)hexan-1-one (4-MPHP), 4-methyl-1-phenyl-2-(pyrrolidin-1-yl)pentan-1-one (α-PiHP) and 2-(methylamino)-1-(4-methylphenyl)pentan-1-one (4-MPD)

2022 ◽  
Vol 78 (1) ◽  
Author(s):  
Marcin Rojkiewicz ◽  
Piotr Kuś ◽  
Maria Książek ◽  
Joachim Kusz
Keyword(s):  
Chemical Structure ◽  
Crystallographic Data ◽  
New Psychoactive Substances ◽  
Monoclinic Space Group ◽  
Psychoactive Substances ◽  
Space Group ◽  
X Ray ◽  
X Ray Crystallography ◽  
Analytical Laboratories

Cathinones belong to a group of compounds of great interest in the new psychoactive substances (NPS) market. Constant changes to the chemical structure made by the producers of these compounds require a quick reaction from analytical laboratories in ascertaining their characteristics. In this article, three cathinone derivatives were characterized by X-ray crystallography. The investigated compounds were confirmed as: 1-[1-(4-methylphenyl)-1-oxohexan-2-yl]pyrrolidin-1-ium chloride (1, C17H26NO+·Cl−, the hydrochloride of 4-MPHP), 1-(4-methyl-1-oxo-1-phenylpentan-2-yl)pyrrolidin-1-ium chloride (2; C16H24NO+·Cl−, the hydrochloride of α-PiHP) and methyl[1-(4-methylphenyl)-1-oxopentan-2-yl]azanium chloride (3; C13H20NO+·Cl−, the hydrochloride of 4-MPD). All the salts crystallize in a monoclinic space group: 1 and 2 in P21/c, and 3 in P21/n. To the best of our knowledge, this study provides the first detailed and comprehensive crystallographic data on salts 1–3.

Synthesis, characterization and crystal structures of novel fluorinated di(thiazolyl)benzene derivatives

2019 ◽  
Vol 6 (6) ◽  
pp. 780-790 ◽  
Author(s):  
Maciej Barłóg ◽  
Ihor Kulai ◽  
Xiaozhou Ji ◽  
Nattamai Bhuvanesh ◽  
Somnath Dey ◽  
...  
Keyword(s):  
Crystal Structures ◽  
Benzene Derivatives ◽  
Stille Coupling ◽  
X Ray ◽  
X Ray Crystallography ◽  
Microwave Assisted

A series of 11 novel fluorinated and non-fluorinated di(thiazolyl)benzenes have been synthesized via microwave assisted Stille coupling and characterized using X-ray crystallography.

Synthesis and crystal structures of three novel benzimidazole/benzoindolizine hybrids

2016 ◽  
Vol 71 (3) ◽  
pp. 231-239 ◽  
Author(s):  
Roumaissa Belguedj ◽  
Sofiane Bouacida ◽  
Hocine Merazig ◽  
Ali Belfaitah ◽  
Aissa Chibani ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Nmr Spectroscopy ◽  
Crystal Structures ◽  
Dipolar Cycloaddition ◽  
Dimethyl Acetylenedicarboxylate ◽  
X Ray ◽  
X Ray Crystallography ◽  
Dimethyl Maleate

AbstractThree benzoindolizine derivatives, 1, 2, and 3, were obtained via 1,3-dipolar cycloaddition. The reaction of 1-(2′-benzimidazolylmethyl)isoquinolinium ylides with dimethyl acetylenedicarboxylate gave a mixture of pyrrolo[2,1-a]isoquinoline-1,2-dicarboxylate (1) and 1,10b-dihydropyrrolo[2,1-a]isoquinoline-1,2-dicarboxylate (2) derivatives containing a benzimidazole moiety. The reaction of this isoquinolinium N-ylide with dimethyl maleate gave an unexpected 2,3-dihydropyrrolo[2,1-a]isoquinoline-1,2-dicarboxylate (3). The structures of all reported compounds have been examined by X-ray crystallography, mass spectrometry, and NMR spectroscopy.

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