2.6 A X-ray crystal structure of human p53R2, a p53-inducible ribonucleotide reductase .
Human p53R2 (hp53R2) is a 351-residue p53-inducible ribonucleotide reductase (RNR) small subunit. It shares >80% sequence identity with hRRM2, the small RNR subunit responsible for normal maintenance of the deoxyribonucleotide (dNTP) pool used for DNA replication, which is active during the S phase in a cell cycle-dependent fashion. But rather than cyclic dNTP synthesis, hp53R2 has been shown to supply dNTPs for DNA repair to cells in G0-G1 in a p53-dependent fashion. The first X-ray crystal structure of hp53R2 is determined to 2.6 A, in which monomers A and B exhibit mono- and binuclear iron occupancy, respectively. The pronounced structural differences at three regions between hp53R2 and hRRM2 highlight the possible regulatory role in iron assimilation and help explain previously observed physical and biochemical differences in the mobility and accessibility of the radical iron center, as well as radical transfer pathways between the two enzymes. The sequence-structure-function correlations that differentiate hp53R2 and hRRM2 are revealed for the first time. Insight gained from this structural work will be used in the identification of biological function, regulation mechanism, and inhibitor selection in RNR small subunits.
Smith
Peter
P
Department of Chemistry, University of California, Irvine, California 92697, USA.
Zhou
Bingsen
B
Ho
Nam
N
Yuan
Yate-Ching
YC
Su
Leila
L
Tsai
Shiou-Chuan
SC
Yen
Yun
Y
D001665:Binding Sites; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000235:genetics; D018360:Crystallography, X-Ray; D003545:Cysteine / Q000737:chemistry; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000627:therapeutic use; D006801:Humans; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D007501:Iron / Q000737:chemistry; D008958:Models, Molecular; D020836:Protein Structure, Quaternary; D017433:Protein Structure, Secondary; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics; D012262:Ribonucleoside Diphosphate Reductase / Q000737:chemistry; D012264:Ribonucleotide Reductases / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000235:genetics; D055672:Static Electricity; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D014443:Tyrosine / Q000737:chemistry
D018797:Cell Cycle Proteins; D004791:Enzyme Inhibitors; D011994:Recombinant Proteins; D016159:Tumor Suppressor Protein p53; D014443:Tyrosine; D007501:Iron; C405947:RRM2B protein, human; D012264:Ribonucleotide Reductases; C093713:ribonucleotide reductase M2; D012262:Ribonucleoside Diphosphate Reductase; D003545:Cysteine