Structural mechanism of allosteric substrate specificity regulation in a ribonucleotide reductase.
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.
Department of Biochemistry and Biophysics, Stockholm University, S-106 91 Stockholm, Sweden.
Karl-Magnus
KM
Larsson
Albert
A
Jordan
Rolf
R
Eliasson
Peter
P
Reichard
Derek T
DT
Logan
Pär
P
Nordlund
D000255:Adenosine Triphosphate / Q000737:chemistry; D000495:Allosteric Site; D000595:Amino Acid Sequence; D001665:Binding Sites; D002384:Catalysis; D004247:DNA / Q000737:chemistry; D004260:DNA Repair; D019143:Evolution, Molecular; D006160:Guanosine Triphosphate / Q000737:chemistry; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011485:Protein Binding; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D012264:Ribonucleotide Reductases / Q000737:chemistry*; D017386:Sequence Homology, Amino Acid; D013379:Substrate Specificity; D020124:Thermotoga maritima / Q000201:enzymology; D013942:Thymine Nucleotides / Q000737:chemistry
D013942:Thymine Nucleotides; D006160:Guanosine Triphosphate; D000255:Adenosine Triphosphate; D004247:DNA; D012264:Ribonucleotide Reductases; C024157:thymidine 5'-triphosphate