Studies on Flavin Derivatives. III. The Crystal and Molecular Structure of 9-Bromo-5-hydro- 1,3,7,8,10-pentamethyl-1,5-dihydroalloxazine.

Norrestam, R.; Glehn, Marianne von; Hagman, Lars‐Ove; Kierkegaard, Peder; Gustavii, Klas; Junggren, Ulf; Lamm, Bo; Samuelsson, Benny

doi:10.3891/acta.chem.scand.23-2199

Cited by 12 publications

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“…The molecular structure of isoalloxazine in the reduced state has been studied since the 1960s and is proposed to vibrate along the axis formed between the N5 and N10 atoms, mimicking the wing movements of a butterfly (Dudley et al 1964; Tauscher et al 1973). The atomic structures of several polysubstituted isoalloxazines in the reduced form reveal relatively low bending angles along the N5‐N10 axis deviating from planarity by 12.7–35.5 degrees (Norrestam et al 1969a, 1969b; Leijonmark and Werner 1971; Norrestam and Glehn 1972; Glehn et al 1977; Porter and Voet 1978). Based on nuclear magnetic resonance (NMR) spectra, Vervoort et al proposed that the isoalloxazine ring of reduced flavin mononucleotide bound to luciferase is highly planar and rigid (Vervoort et al 1986).…”

Section: Resultsmentioning

confidence: 99%

Modeling of the bacterial luciferase‐flavin mononucleotide complex combining flexible docking with structure‐activity data

et al. 2001

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Although the crystal structure of Vibrio harveyi luciferase has been elucidated, the binding sites for the flavin mononucleotide and fatty aldehyde substrates are still unknown. The determined location of the phosphate-binding site close to Arg 107 on the ␣ subunit of luciferase is supported here by point mutagenesis. This information, together with previous structure-activity data for the length of the linker connecting the phosphate group to the isoalloxazine ring represent important characteristics of the luciferasebound conformation of the flavin mononucleotide. A model of the luciferase-flavin complex is developed here using flexible docking supplemented by these structural constraints. The location of the phosphate moiety was used as the anchor in a flexible docking procedure performed by conformation search by using the Monte Carlo minimization approach. The resulting databases of energy-ranked feasible conformations of the luciferase complexes with flavin mononucleotide, -phosphopentylflavin, -phosphobutylflavin, and -phosphopropylflavin were filtered according to the structure-activity profile of these analogs. A unique model was sought not only on energetic criteria but also on the geometric requirement that the isoalloxazine ring of the active flavin analogs must assume a common orientation in the luciferase-binding site, an orientation that is also inaccessible to the inactive flavin analog. The resulting model of the bacterial luciferase-flavin mononucleotide complex is consistent with the experimental data available in the literature. Specifically, the isoalloxazine ring of the flavin mononucleotide interacts with the Ala 74-Ala 75 cis-peptide bond as well as with the Cys 106 side chain in the ␣ subunit of luciferase. The model of the binary complex reveals a distinct cavity suitable for aldehyde binding adjacent to the isoalloxazine ring and flanked by other key residues (His 44 and Trp 250) implicated in the active site.Keywords: Bacterial luciferase; flavin mononucleotide; flexible docking; structural constraints Bacterial luciferase, a heterodimeric protein constituted of two homologous subunits (␣ and ␤), catalyzes the oxidation of reduced flavin mononucleotide and fatty aldehyde in a process that reduces molecular oxygen to water and releases energy in the form of light (∼490 nm). Both the ␣ (LuxA) and ␤ (LuxB) subunits fold into (␤/␣) 8 barrels in the crystal structures of bacterial luciferase from Vibrio harveyi (Fisher et al. 1995(Fisher et al. , 1996. The ␣ subunit is primarily responsible for kinetic properties; however, the presence of the ␤ subunit is essential for high catalytic efficiency (Cline and Hastings 1972;Li et al. 1993). The active site thus is believed to be formed by residues in the ␣ subunit with the phosphate moiety of flavin mononucleotide anchored at an electron dense inorganic phosphate site detected on LuxA (Fisher et al. 1995). Another critical factor controlling the biolumi-

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Section: Resultsmentioning

confidence: 99%

Modeling of the bacterial luciferase‐flavin mononucleotide complex combining flexible docking with structure‐activity data

et al. 2001

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Heterocyclische Systeme mit acht π-Elektronen. Synthese, Eigenschaften, Bedeutung

Schmidt

1975

Angew. Chem.

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Die Begriffe ,,aromatisch" und ,,antiaromatisch" haben in den letzten Jahren ein breites lnteresse gefunden. Unabhangig von der hiufig gefiihrten Diskussion um Worte bleibt als Tatbestand : Der Energieinhalt ist bei planaren Systemen mit cyclischer Elektronendelokalisation von der Zdhl und von der Orbitalwechselwirkung der beteiligten Elektronen abhangig. Diesem Fortschrittsbericht liegt der Gedanke zugrunde, daB die elektronische Destabilisierung von Systemen mit acht x-Elektronen bei sechsgliedrigen Ringen aus sterischen und elektronischen Grunden besonders ausgepragt sein sollte. Dabei komnien vor allem anionische, aber auch neutrale Heterocyclen mit Heteroringgliedern, welche in das x-System delokalisierbare Elektronenpaare besitzen, in Betracht. Die Erzeugung und Reaktivitat solcher Systeme wird untersucht und ihre biologische Bedeutung diskutiert.

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Heterocyclic Systems Having Eight π‐Electrons. Synthesis, Properties, and Significance

Schmidt

1975

Angew. Chem. Int. Ed. Engl.

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The terms "aromatic" and "antiaromatic" have attracted widespread interest in recent years. After all the discussion about the meaning of words, one fact remains: the energy content of planar systems displaying cyclic electron delocalization depends upon the number of, and the orbital interactions between, the participating electrons. The concept underlying this progress report is that the electronic destabilization of systems having eight x-electrons should be especially pronounced in the case of six-membered rings for steric and electronic reasons. Such systems are found primarily in anionic, but also in neutral, heterocycles containing hetero ring members which possess electron pairs capable of delocalizing into the x-system. The production and reactivity of such systems are investigated and their biological significance discussed.

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Studies on Flavin Derivatives. III. The Crystal and Molecular Structure of 9-Bromo-5-hydro- 1,3,7,8,10-pentamethyl-1,5-dihydroalloxazine.

Cited by 12 publications

References 0 publications

Modeling of the bacterial luciferase‐flavin mononucleotide complex combining flexible docking with structure‐activity data

Modeling of the bacterial luciferase‐flavin mononucleotide complex combining flexible docking with structure‐activity data

Heterocyclische Systeme mit acht π-Elektronen. Synthese, Eigenschaften, Bedeutung

Heterocyclic Systems Having Eight π‐Electrons. Synthesis, Properties, and Significance

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