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Crystal structure of methylenetetrahydromethanopterin reductase (Mer) in complex with coenzyme F₄₂₀: Architecture of the F₄₂₀/FMN binding site of enzymes within the nonprolyl cis-peptide containing bacterial luciferase family

¹ Max-Planck-Institut für terrestrische Mikrobiologie and Laboratorium für Mikrobiologie, Fachbereich Biologie, Philipps-Universität, D-35043 Marburg, Germany
² Max-Planck-Institut für Biophysik, D-60438 Frankfurt/Main, Germany

(RECEIVED December 16, 2004; FINAL REVISION March 22, 2005; ACCEPTED March 25, 2005)

Methylenetetratetrahydromethanopterin reductase (Mer) is involved in CO₂ reduction to methane in methanogenic archaea and catalyses the reversible reduction of methylenetetrahydromethanopterin (methylene-H₄MPT) to methyl-H₄MPT with coenzyme F₄₂₀H₂, which is a reduced 5'-deazaflavin. Mer was recently established as a TIM barrel structure containing a nonprolyl cis-peptide bond but the binding site of the substrates remained elusive. We report here on the crystal structure of Mer in complex with F₄₂₀ at 2.6 Å resolution. The isoalloxazine ring is present in a pronounced butterfly conformation, being induced from the Re-face of F₄₂₀ by a bulge that contains the non-prolyl cis-peptide bond. The binding mode of F₄₂₀ is very similar to that in F₄₂₀-dependent alcohol dehydrogenase Adf despite the low sequence identity of 21%. Moreover, binding of F₄₂₀ to the apoenzyme was only associated with minor conformational changes of the polypeptide chain. These findings allowed us to build an improved model of FMN into its binding site in bacterial luciferase, which belongs to the same structural family as Mer and Adf and also contains a nonprolyl cis-peptide bond in an equivalent position.

Keywords: Methylenetetrahydromethanopterin reductase; bacterial luciferase; crystal structure; nonprolyl cis-peptide bond coenzyme F₄₂₀; FMN

Abbreviations: FMN, flavin mononucleotide • FAD, flavin adenine dinucleotide • F₄₂₀, coenzyme F₄₂₀ • NADP, nicotinamide adenine dinucleotide phosphate • H₄ MPT, tetrahydromethanopterin • Mer, N⁵,N¹⁰-methylenetetrahydromethanopterin reductase • bMer, Mer from Methanosarcina barkeri, tMer, Mer from Methanothermobacter marburgensis • kMer, Mer from Methanopyrus kandleri • Adf, F₄₂₀-dependent alcohol dehydrogenase • Lux, bacterial luciferase • SsuD, FMN-dependent alkanesulfonate monooxygenase • MetF, NADP-dependent FAD harboring N⁵,N¹⁰-methylenetetrahydrofolate reductase • IR, insertion regions in the Mer structures • PEG, polyethylene glycol

Article published online ahead of print. Article and publication date are at http://www.proteinscience.org/cgi/doi/10.1110/ps.041289805.

Reprint requests to: Seigo Shima, Max-Planck-Institut für terrestrische Mikrobiologie, Karl-von-Frisch Strasse, D-35043 Marburg, Germany; e-mail: shima{at}staff.uni-marburg.de; fax: 49-6421-178199; or Ulrich Ermler, Max-Planck-Institut für Biophysik, Max-von-Laue-Strasse 3, D-60438 Frankfurt/Main, Germany; e-mail: uli.ermler{at}mpibp-frankfurt.mpg.de; fax: 49-69-6303-1002.

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