The Crystal Structure of Thermotoga maritima Class III Ribonucleotide Reductase Lacks a Radical Cysteine Pre-Positioned in the Active Site

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The Crystal Structure of Thermotoga maritima Class III Ribonucleotide Reductase Lacks a Radical Cysteine Pre-Positioned in the Active Site

Aurelius, Oskar (author): Lund University,Lunds universitet,Biokemi och Strukturbiologi,Centrum för Molekylär Proteinvetenskap,Kemiska institutionen,Institutioner vid LTH,Lunds Tekniska Högskola,Biochemistry and Structural Biology,Center for Molecular Protein Science,Department of Chemistry,Departments at LTH,Faculty of Engineering, LTH

Johansson, Renzo (author): Lund University,Lunds universitet,Biokemi och Strukturbiologi,Centrum för Molekylär Proteinvetenskap,Kemiska institutionen,Institutioner vid LTH,Lunds Tekniska Högskola,Biochemistry and Structural Biology,Center for Molecular Protein Science,Department of Chemistry,Departments at LTH,Faculty of Engineering, LTH

Bågenholm, Viktoria (author): Lund University,Lunds universitet,Biokemi och Strukturbiologi,Centrum för Molekylär Proteinvetenskap,Kemiska institutionen,Institutioner vid LTH,Lunds Tekniska Högskola,Biochemistry and Structural Biology,Center for Molecular Protein Science,Department of Chemistry,Departments at LTH,Faculty of Engineering, LTH

Lundin, Daniel, 1965- (author): Stockholms universitet,Institutionen för biokemi och biofysik,Stockholm University,Jarone Pinhassi

Tholander, Fredrik (author): Karolinska Institutet

Balhuizen, Alexander (author): Lund University,Lunds universitet,Celiaki och diabetes,Forskargrupper vid Lunds universitet,Celiac Disease and Diabetes Unit,Lund University Research Groups

Beck, Tobias (author): University of Göttingen, Germany

Sahlin, Margareta (author): Stockholms universitet,Institutionen för biokemi och biofysik,Stockholm University

Sjöberg, Britt-Marie (author): Stockholms universitet,Institutionen för biokemi och biofysik,Stockholm University

Mulliez, Etienne (author): Institut de Recherches en Technologies et Sciences pour le Vivant (iRTSV), France

Logan, Derek (author): Lund University,Lunds universitet,Biokemi och Strukturbiologi,Centrum för Molekylär Proteinvetenskap,Kemiska institutionen,Institutioner vid LTH,Lunds Tekniska Högskola,Biochemistry and Structural Biology,Center for Molecular Protein Science,Department of Chemistry,Departments at LTH,Faculty of Engineering, LTH

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2015-07-06
2015
English.
In: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 10:7

Related links:: https://doi.org/10.1...; show more...; https://lnu.diva-por... (primary) (Raw object); https://journals.plo...; https://portal.resea... (primary) (free); http://dx.doi.org/10... (free); https://urn.kb.se/re...; https://doi.org/10.1...; https://lup.lub.lu.s...; http://kipublication...; https://urn.kb.se/re...; show less...

Journal article (peer-reviewed)

Abstract Subject headings

Ribonucleotide reductases (RNRs) catalyze the reduction of ribonucleotides to deoxyribonucleotides, the building blocks for DNA synthesis, and are found in all but a few organisms. RNRs use radical chemistry to catalyze the reduction reaction. Despite RNR having evolved several mechanisms for generation of different kinds of essential radicals across a large evolutionary time frame, this initial radical is normally always channelled to a strictly conserved cysteine residue directly adjacent to the substrate for initiation of substrate reduction, and this cysteine has been found in the structures of all RNRs solved to date. We present the crystal structure of an anaerobic RNR from the extreme thermophile Thermotoga maritima (tmNrdD), alone and in several complexes, including with the allosteric effector dATP and its cognate substrate CTP. In the crystal structure of the enzyme as purified, tmNrdD lacks a cysteine for radical transfer to the substrate pre-positioned in the active site. Nevertheless activity assays using anaerobic cell extracts from T. maritima demonstrate that the class III RNR is enzymatically active. Other genetic and microbiological evidence is summarized indicating that the enzyme is important for T. maritima. Mutation of either of two cysteine residues in a disordered loop far from the active site results in inactive enzyme. We discuss the possible mechanisms for radical initiation of substrate reduction given the collected evidence from the crystal structure, our activity assays and other published work. Taken together, the results suggest either that initiation of substrate reduction may involve unprecedented conformational changes in the enzyme to bring one of these cysteine residues to the expected position, or that alternative routes for initiation of the RNR reduction reaction may exist. Finally, we present a phylogenetic analysis showing that the structure of tmNrdD is representative of a new RNR subclass IIIh, present in all Thermotoga species plus a wider group of bacteria from the distantly related phyla Firmicutes, Bacteroidetes and Proteobacteria.

Subject headings

NATURVETENSKAP -- Biologi -- Strukturbiologi (hsv//swe)
NATURAL SCIENCES -- Biological Sciences -- Structural Biology (hsv//eng)
NATURVETENSKAP -- Biologi -- Biokemi och molekylärbiologi (hsv//swe)
NATURAL SCIENCES -- Biological Sciences -- Biochemistry and Molecular Biology (hsv//eng)
NATURVETENSKAP -- Biologi (hsv//swe)
NATURAL SCIENCES -- Biological Sciences (hsv//eng)
NATURVETENSKAP -- Kemi (hsv//swe)
NATURAL SCIENCES -- Chemical Sciences (hsv//eng)

Keyword

Sequence motif analysis
Crystal structure
Cysteine
Enzyme structure
Ribonucleotides
Chemical radicals
Electron density
Thermotoga
Natural Science
Naturvetenskap

Publication and Content Type

ref (subject category)
art (subject category)

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By the author/editor: Aurelius, Oskar; Johansson, Renzo; Bågenholm, Vikto ...; Lundin, Daniel, ...; Tholander, Fredr ...; Balhuizen, Alexa ...; show more...; Beck, Tobias; Sahlin, Margaret ...; Sjöberg, Britt-M ...; Mulliez, Etienne; Logan, Derek; show less...

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NATURAL SCIENCES: NATURAL SCIENCES; and Biological Scien ...; and Structural Biolo ...

NATURAL SCIENCES: NATURAL SCIENCES; and Biological Scien ...; and Biochemistry and ...

NATURAL SCIENCES: NATURAL SCIENCES; and Biological Scien ...

NATURAL SCIENCES: NATURAL SCIENCES; and Chemical Science ...

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