Larsson Karl-Magnus, Jordan Albert, Eliasson Rolf, Reichard Peter, Logan Derek T, Nordlund Pär
Department of Biochemistry and Biophysics, Stockholm University, S-106 91 Stockholm, Sweden.
Nat Struct Mol Biol. 2004 Nov;11(11):1142-9. doi: 10.1038/nsmb838. Epub 2004 Oct 10.
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.
核糖核苷酸还原酶（RNRs）催化核糖核苷酸还原为脱氧核糖核苷酸，而脱氧核糖核苷酸构成了用于DNA合成和修复的前体库。这些库中的失衡会增加突变率，对细胞有害。平衡的前体库主要通过调节RNR底物特异性来维持。在这里，通过来自嗜热栖热菌的二聚体钴胺素依赖性RNR的结构揭示了变构底物特异性调节的分子机制，该结构既有与四对效应物-底物核苷酸的复合物，也有仅与效应物的三种复合物。该机制基于环2的灵活性，环2是一个关键结构元件，它在特异性效应物和底物核苷酸之间形成桥梁。由于不同的效应物及其同源底物稳定了特定的离散环2构象，从而实现了底物特异性。底物特异性调节机制可能对大多数I类和II类RNRs来说是普遍存在的。
