Intermolecular Effects in Crystals of 11-(Trifluoromethyl)-15,16-dihydrocyclopenta[a]phenanthren-17-one

Shimoni, Liat; Carrell, H. L.; Glusker, Jenny P.; Coombs, Maurice M.

doi:10.1021/ja00097a025

Cited by 96 publications

(46 citation statements)

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“…Halothane has the potential to act as a hydrogen bond acceptor via one or more of its halogen atoms (53)(54)(55), which may interact favorably with either indole ring hydrogens or with the cysteine sulfhydryl group. While the detailed structure of the complex formed between halothane and (AR 2 ) 2 remains to be determined, it is clear that the anesthetic resides in the vicinity of the hydrophobic core tryptophan residues as designed, since fluorescence quenching by heavy atoms is a short-range phenomenon occurring over a distances less than 3-5 Å (56,57).…”

Section: Discussionmentioning

confidence: 99%

A Designed Cavity in the Hydrophobic Core of a Four-α-Helix Bundle Improves Volatile Anesthetic Binding Affinity

et al. 1998

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The structural features of protein binding sites for volatile anesthetics are being explored using a defined model system consisting of a four-alpha-helix bundle scaffold with a hydrophobic core. Earlier work has demonstrated that a prototype hydrophobic core is capable of binding the volatile anesthetic halothane. Exploratory work on the design of an improved affinity anesthetic binding site is presented, based upon the introduction of a simple cavity into a prototype (alpha 2)2 four-alpha-helix bundle by replacing six core leucines with smaller alanines. The presence of such a cavity increases the affinity (Kd = 0.71 +/- 0.04 mM) of volatile anesthetic binding to the designed bundle core by a factor of 4.4 as compared to an analogous bundle core lacking such a cavity (Kd = 3.1 +/- 0.4 mM). This suggests that such packing defects present on natural proteins are likely to be occupied by volatile general anesthetics in vivo. Replacing six hydrophobic core leucine residues with alanines results in a destabilization of the folded bundle by 1.7-2.7 kcal/mol alanine, although the alanine-substituted bundle still exhibits a high degree of thermodynamic stability with an overall folded conformational delta GH2O = 14.3 +/- 0.8 kcal/mol. Covalent attachment of the spin label MTSSL to cysteine residues in the alanine-substituted four-alpha-helix bundle indicates that the di-alpha-helical peptides dimerize in an anti orientation. The rotational correlation time of the four-alpha-helix bundle is 8.1 +/- 0.5 ns, in line with earlier work on similar peptides. Fluorescence, far-UV circular dichroism, and Fourier transform infrared spectroscopies verified the hydrophobic core location of the tryptophan and cysteine residues, showing good agreement between experiment and design. These small synthetic proteins may prove useful for the study of the structural features of small molecule binding sites.

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Section: Discussionmentioning

confidence: 99%

A Designed Cavity in the Hydrophobic Core of a Four-α-Helix Bundle Improves Volatile Anesthetic Binding Affinity

et al. 1998

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“…In this case intramolecular strains caused by repulsion between protons in pseudo fjord-region are balanced by shortening some bonds which acquire more double bond character and by enlarging exocyclic angles within pseudo fjord-region (Table 2). It should be noted that these angles and bond lengths were comparable to those in bay-region of muta-and carcinogenic cyclopenta[a]phenanthrene derivatives (27). For example: 1,11-methano-15,16-dihydrocyclopenta[a]phenanthren-17-one which is planar but severing bond angle distortions possess an Iball index = 16 (28).…”

Section: Discussionmentioning

confidence: 55%

“…Standard PCR reaction conditions and thermal cycling protocol were described in the papers cited in Table 1. In order to adopt a more semi-quantitative approach for analysis of the gene expression, both CYP1A and ß-actin gene (external standard) were amplified using a series of cycle numbers (20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30). Following this procedure the optimal cycle number was determined and subsequently employed in the expression studies.…”

Section: Total Rna Isolation and Semi-quantitative Rt-pcrmentioning

confidence: 99%

MOLECULAR GEOMETRY,CYP1AGENE INDUCTION AND CLASTOGENIC ACTIVITY OF CYCLOPENTA[c]PHENANTHRENE IN RAINBOW TROUT

Brzuzan

Jurczyk

Woźny

et al. 2006

Polycyclic Aromatic Compounds

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345 346 P. Brzuzan et al. intramolecular strains caused by repulsion between protons in the pseudo fjord-region are balanced by both the shortening of some bonds which acquire more double bond character, and by the enlargement of exocyclic angles within the pseudo fjord-region. The activity of CP[c]Ph was investigated in vivo in rainbow trout, Oncorhynchus mykiss. The CYP1A mRNA levels following 48h-treatment with CP[c]Ph or benzo[a]pyrene (B[a]P; positive control) were determined and compared with incidences of clastogenic changes observed in the peripheral blood erythrocytes. We have found that the ability to induce CYP1A by these PAH compounds is positively correlated with the incidences of clastogenic changes in rainbow trout erythrocytes.

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“…In contrast to anionic fluoride, organic fluorine is a poor hydrogen‐bond acceptor. X‐ray diffraction analyses (Murray‐Rust et al 1983; Shimoni et al 1994) as well as extensive surveys of structural databases (Shimoni and Glusker 1994; Howard et al 1996; Dunitz and Taylor 1997) have revealed but few crystalline organofluorine compounds that display short C–F···H–X distances, where X = C, N, or O. In addition, a presumably intimate C–F···H–N interaction does not stabilize DNA double helices (Moran et al 1997).…”

Section: Resultsmentioning

confidence: 99%

2005 Emil Thomas Kaiser Award

Raines

2006

Protein Science

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Collagen is the most abundant protein in animals. The conformational stability of the collagen triple helix is enhanced by the hydroxyl group of its prevalent (2S,4R)-4-hydroxyproline residues. For 25 years, the prevailing paradigm had been that this enhanced stability is due to hydrogen bonds mediated by bridging water molecules. We tested this hypothesis with synthetic collagen triple helices containing 4-fluoroproline residues. The results have unveiled a wealth of stereoelectronic effects that contribute markedly to the stability of collagen, as well as other proteins. This new understanding is leading to synthetic collagens for a variety of applications in biotechnology and biomedicine.

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Intermolecular Effects in Crystals of 11-(Trifluoromethyl)-15,16-dihydrocyclopenta[a]phenanthren-17-one

Cited by 96 publications

References 0 publications

A Designed Cavity in the Hydrophobic Core of a Four-α-Helix Bundle Improves Volatile Anesthetic Binding Affinity

A Designed Cavity in the Hydrophobic Core of a Four-α-Helix Bundle Improves Volatile Anesthetic Binding Affinity

MOLECULAR GEOMETRY,CYP1AGENE INDUCTION AND CLASTOGENIC ACTIVITY OF CYCLOPENTA[c]PHENANTHRENE IN RAINBOW TROUT

2005 Emil Thomas Kaiser Award

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