scholarly journals Filling of a water-free void explains the allosteric regulation of the β1-adrenergic receptor by cholesterol

2021 ◽  
Author(s):  
Layara Akemi Abiko ◽  
Raphael Dias Teixeira ◽  
Sylvain Engilberge ◽  
Anne Grahl ◽  
Stephan Grzesiek
Keyword(s):  
Adrenergic Receptor ◽  
Binding Pocket ◽  
Solution Nmr ◽  
Allosteric Modulator ◽  
Active Conformation ◽  
X Ray ◽  
X Ray Crystallography ◽  
Nmr Data ◽  
Negative Allosteric Modulator ◽  
Cholesteryl Hemisuccinate

Proteins often contain cavities, which are usually assumed to be water-filled. Recent high-pressure NMR results indicate that the preactive conformation of the β1-adrenergic receptor (β1AR) contains completely empty cavities (dry voids) of about ~100 Å3 volume, which disappear in the active conformation of the receptor. Here we have localized these cavities by X-ray crystallography on xenon-derivatized β1AR crystals. One of the cavities coincides with the binding pocket of cholesterol. Solution NMR data show that addition of the soluble cholesterol analog cholesteryl hemisuccinate (CHS) impedes the formation of the active conformation of the receptor by blocking conserved GPCR microswitches. This wedge-like action explains the function of the cellularly highly abundant cholesterol as a negative allosteric modulator of β1AR. The detailed understanding of GPCR regulation by cholesterol via filling of a dry void and the easy scouting for such voids by xenon may provide new routes for the development of allosteric drugs.

Tele-Substitution Reactions in the Synthesis of a Promising Class of Antimalarials

2020 ◽  
Author(s):  
Marat Korsik ◽  
Edwin Tse ◽  
David Smith ◽  
William Lewis ◽  
Peter J. Rutledge ◽  
...  
Keyword(s):  
Heterocyclic Ring ◽  
Ring System ◽  
Substitution Reactions ◽  
Laboratory Notebook ◽  
Polar Solvents ◽  
X Ray ◽  
X Ray Crystallography ◽  
The Core ◽  
Nmr Data

<p></p><p>We have discovered and studied a <i>tele</i>substitution reaction in a biologically important heterocyclic ring system. Conditions that favour the <i>tele</i>-substitution pathway were identified: the use of increased equivalents of the nucleophile or decreased equivalents of base, or the use of softer nucleophiles, less polar solvents and larger halogens on the electrophile. Using results from X-ray crystallography and isotope labelling experiments a mechanism for this unusual transformation is proposed. We focused on this triazolopyrazine as it is the core structure of the <i>in vivo </i>active anti-plasmodium compounds of Series 4 of the Open Source Malaria consortium.</p> <p> </p> <p>Archive of the electronic laboratory notebook with the description of all conducted experiments and raw NMR data could be accessed via following link <a href="https://ses.library.usyd.edu.au/handle/2123/21890">https://ses.library.usyd.edu.au/handle/2123/21890</a> . For navigation between entries of laboratory notebook please use file "Strings for compounds in the article.pdf" that works as a reference between article codes and notebook codes, also this file contain SMILES for these compounds. </p><br><p></p>

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.

Computational challenges for macromolecular structure determination by X-ray crystallography and solution NMRspectroscopy

1993 ◽  
Vol 26 (1) ◽  
pp. 49-125 ◽  
Author(s):  
Axel T. Brünger ◽  
Michael Nilges
Keyword(s):  
Nmr Spectroscopy ◽  
Structure Determination ◽  
Solution Nmr ◽  
Macromolecular Structure ◽  
X Ray ◽  
X Ray Crystallography ◽  
The Past ◽  
Solution Nmr Spectroscopy

Macromolecular structure determination by X-ray crystallography and solution NMR spectroscopy has experienced unprecedented growth during the past decade.

scholarly journals Tris(phosphan)-Nickel(0)-Ethen-Komplexe (dmpe)(PR3)Ni(C2H4). Molekülstruktur des (dmpe)(PØ3 )Ni(C2H4)/ Tris(phosphane)-nickel(0)-ethene Complexes (dmpe)(PR3)Ni(C2H4). Molecular Structure of (dmpe)(PO3)Ni(C2H4)

1984 ◽  
Vol 39 (8) ◽  
pp. 1076-1081 ◽  
Author(s):  
Klaus R. Pörschke ◽  
Richard Mynott ◽  
Carl Krüger ◽  
M. J. Romão
Keyword(s):  
Molecular Structure ◽  
Ligand Exchange ◽  
Crystal And Molecular Structure ◽  
Exchange Reactions ◽  
Tetrahedral Geometry ◽  
X Ray ◽  
X Ray Crystallography ◽  
Nmr Data

AbstractSynthesis and properties of tris(phosphane)(ethene)nickel(0) complexes (dmpe)(PR3)Ni(C2H4) (R = CH3(4), c-C6H11(5), and C6H5 (6)) are reported. In solution. 4-6 are thermolabile and undergo ligand exchange reactions affording tetrakis(phosphane)nickel(0 ) and bis(phosphane)- (ethene)nickel(0) complexes. 1H, 13C, and 31P NMR data of 4-6 confirm the tetrahedral geometry around nickel. For 6 , the crystal and molecular structure has been determined by X-ray crystallography.

scholarly journals Coordination studies of 1,2-bis(diphenylphosphino)ethane with di-μ-hydroxo dinuclear complexes of tungsten(IV) and molybdenum(IV)

2016 ◽  
Vol 81 (1) ◽  
pp. 47-55
Author(s):  
Makoto Minato ◽  
Takashi Ito ◽  
Jian-Guo Ren
Keyword(s):  
31P Nmr ◽  
Product Distribution ◽  
Dinuclear Complex ◽  
Nucleophilic Attack ◽  
Dinuclear Complexes ◽  
X Ray ◽  
X Ray Crystallography ◽  
Phosphine Complexes ◽  
Nmr Data ◽  
Reaction Profile

The new trifluoroethoxo phosphine complexes [Cp2M(?1-dppe)(CF3CH2O)]+ and [Cp2(CF3CH2O)M(?-dppe)MCp2(CF3CH2O)]2+ (M = Mo or W, Cp = ?-C5H5 and dppe = Ph2PCH2CH2PPh2) have been prepared by reaction of cationic di-?-hydroxo dinuclear complex of molybdenocene or tungstenocene [Cp2M(?-OH)2MCp2]2+ with dppe. From the 1H and 31P NMR data, the configurations of the products could be assigned. Furtheremore, X-ray crystallography was used to definitively identify one of the product [Cp2(CF3CH2O)Mo(?-dppe)MoCp2(CF3CH2O)]2+, which crystallizes in space group P21/c(#14) with a = 12.230(5) ?, b = 11.149(5) ?, c = 28.966(7) ?, ? = 101.07(3)?, V = 3876(2) ?3, and Z = 2. It was ascertained that the amount of dppe added to the reaction mixture could influence the product distribution. A mechanism involving initial replacement of the hydroxo ligand by the alkoxo group followed by nucleophilic attack of the phosphine is proposed on the basis of the reaction profile.

scholarly journals Structural insights into the small G-protein Arl13B and implications for Joubert syndrome

2013 ◽  
Vol 457 (2) ◽  
pp. 301-311 ◽  
Author(s):  
Mandy Miertzschke ◽  
Carolin Koerner ◽  
Michael Spoerner ◽  
Alfred Wittinghofer
Keyword(s):  
High Resolution ◽  
G Protein ◽  
Joubert Syndrome ◽  
Active Conformation ◽  
Loss Of Function ◽  
X Ray ◽  
X Ray Crystallography ◽  
Small G Protein ◽  
The Stability ◽  
Structural Insights

Using Arl13B from Chlamydomonas as a model, we show by high resolution X-ray crystallography and biochemical approaches that mutations in patients with Joubert syndrome might lead to loss of function by specifically affecting the stability of the active conformation of Arl13B.

scholarly journals New applications of simulated annealing in X-ray crystallography and solution NMR

Structure ◽  
1997 ◽  
Vol 5 (3) ◽  
pp. 325-336 ◽  
Author(s):  
Axel T Brünger ◽  
Paul D Adams ◽  
Luke M Rice
Keyword(s):  
Simulated Annealing ◽  
Solution Nmr ◽  
X Ray ◽  
X Ray Crystallography ◽  
New Applications

Syntheses, characterization, and X-ray crystal structures of diorganotin(IV) derivatives of 2-pyridinethiolato-N-oxide

2003 ◽  
Vol 81 (10) ◽  
pp. 1070-1075 ◽  
Author(s):  
Chunlin Ma ◽  
Junhong Zhang ◽  
Rufen Zhang
Keyword(s):  
Crystal Structure ◽  
Stacking Interactions ◽  
X Ray ◽  
X Ray Crystallography ◽  
Nmr Data ◽  
Π Stacking ◽  
Oxide Crystal ◽  
Distorted Trigonal Bipyramid ◽  
Π Stacking Interaction ◽  
Derivatives Of

The diorganotin(IV) dichloride reacts with sodium 2-pyridinethiolato-N-oxide in a 1:1 ratio to produce [Me2SnCl(2-SpyO)] (1), [Et2SnCl(2-SpyO)] (2), [Bu2SnCl(2-SpyO)] (3), [Ph2SnCl(2-SpyO)] (4), and [(PhCH2)2SnCl(2- SpyO)] (5). The new complexes have been characterized by elemental analysis and IR and NMR (1H, 119Sn, and 13C) spectroscopy. On the basis of 119Sn NMR data the effective coordination number in solution is five. The structures 1 and 4 have been confirmed by X-ray crystallography. Crystals of 1 are triclinic with space group P[Formula: see text] and those of 4 are monoclinic, P21/n. The tin environment is a distorted trigonal bipyramid with the Cl and oxygen atoms in apical positions. Both complexes exhibit strong π–π stacking interactions. Key words: diorganotin, π–π stacking interaction, 2-pyridinethiolato-N-oxide, crystal structure.

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