Change search
ReferencesLink to record
Permanent link

Direct link
Structural mechanism of allosteric substrate specificity regulation in a ribonucleotide reductase
Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
Show others and affiliations
2004 (English)In: Nature Structural & Molecular Biology, ISSN 1545-9993, E-ISSN 1545-9985, Vol. 11, no 11, 1142-1149 p.Article in journal (Refereed) Published
Abstract [en]

Ribonucleotide reductases (RNRs) catalyze the reduction of ribonucleotides into deoxyribonucleotides, which constitute the precursor pools used for DNA synthesis and repair. Imbalances in these pools increase mutational rates and are detrimental to the cell. Balanced precursor pools are maintained primarily through the regulation of the RNR substrate specificity. Here, the molecular mechanism of the allosteric substrate specificity regulation is revealed through the structures of a dimeric coenzyme B12-dependent RNR from Thermotoga maritima, both in complexes with four effector-substrate nucleotide pairs and in three complexes with only effector. The mechanism is based on the flexibility of loop 2, a key structural element, which forms a bridge between the specificity effector and substrate nucleotides. Substrate specificity is achieved as different effectors and their cognate substrates stabilize specific discrete loop 2 conformations. The mechanism of substrate specificity regulation is probably general for most class I and class II RNRs.

Place, publisher, year, edition, pages
2004. Vol. 11, no 11, 1142-1149 p.
Keyword [en]
National Category
Biochemistry and Molecular Biology Physical Sciences
URN: urn:nbn:se:su:diva-23368DOI: 10.1038/nsmb838OAI: diva2:191541
Available from: 2004-09-22 Created: 2004-09-22 Last updated: 2010-10-28Bibliographically approved
In thesis
1. Allosteric Regulation and Radical Transfer in Ribonucleotide Reductase
Open this publication in new window or tab >>Allosteric Regulation and Radical Transfer in Ribonucleotide Reductase
2004 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The stability of biological life over time requires that the integrity of the genetic material of an organism, the genome, be maintained as it is passed on from one generation to the next. All known cellular life has DNA-based genomes, which are duplicated before each cell division in a process called replication. During and after DNA replication, the integrity of the genetic information is maintained by various proofreading and DNA repair mechanisms. The accuracy of DNA replication and repair is affected by DNA precursor pool imbalances. Feedback regulation of the enzymes involved in DNA precursor biosynthesis has evolved in parallel with the DNA replication and repair system in order to ensure stable precursor pools.

Ribonucleotide reductase (RNR), an enzyme that irreversibly reduces ribonucleotides into deoxyribonucleotides, is a key component in the regulation of the DNA precursor pools. It has sophisticated allosteric regulatory mechanisms that govern both overall activity and substrate specificity, responding to the cellular concentrations of ATP and of the triphosphate forms of the product deoxyribonucleotides, the final DNA precursors.

Using X-ray crystallography we have solved several structures of two ribonucleotide reductases, an anaerobic (class III) enzyme from Bacteriophage T4 and a coenzyme B12-dependent (class II) enzyme from Thermotoga maritima, in complex with various nucleotides and cofactors. The structural information reveals a complete molecular mechanism for the allosteric substrate specificity regulation of class II RNRs which, due to structural homology, is likely also to be valid for the aerobic class I RNRs. The work on the class III RNRs has produced a partial mechanism for the specificity regulation of this class. Both mechanisms utilize Loop 2, a conserved structural element, in the transmission of the allosteric signal.

The discovery of a metal binding domain in the anaerobic RNRs and details of coenzyme B12 binding shed more light on generation and transfer of the protein based radicals used in the reduction reaction.

Place, publisher, year, edition, pages
Stockholm: Institutionen för biokemi och biofysik, 2004. 57 p.
allosteric regulation, substrate specificity, ribonucleotide reductase, radical
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
urn:nbn:se:su:diva-251 (URN)91-7265-931-9 (ISBN)
Public defence
2004-10-13, Magnélisalen, Kemiska övningslaboratoriet, Svante Arrhenius väg 12 A, Stockholm, 14:00 (English)
Available from: 2004-09-22 Created: 2004-09-22 Last updated: 2009-04-06Bibliographically approved

Open Access in DiVA

No full text

Other links

Publisher's full text
By organisation
Department of Biochemistry and Biophysics
In the same journal
Nature Structural & Molecular Biology
Biochemistry and Molecular BiologyPhysical Sciences

Search outside of DiVA

GoogleGoogle Scholar
The number of downloads is the sum of all downloads of full texts. It may include eg previous versions that are now no longer available

Altmetric score

Total: 22 hits
ReferencesLink to record
Permanent link

Direct link