P53R2: Difference between revisions
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{{STRUCTURE_3hf1| PDB=3hf1 | SIZE=400| SCENE=P53R2/P53r2/3 |right|CAPTION=p53R2 complex with Fe and sulfate ions, [[3hf1]] }} | |||
[[Image:3hf1.png|left|200px]] | |||
[[p53R2]] is an oxydoreductase composed of 351 residues, that could be a new target for an anticancer therapy. It is a small subunit of the ribonucleotide reductase (RNR). | |||
RNR catalyses the reduction of the four nucleotides to desoxyribonucleotides. It exists three classes of RNR. Class I RNR is a tetramer composed of the two types of subunits with stoichiometry α2β2 and three subunits have been identified in mammals : | RNR catalyses the reduction of the four nucleotides to desoxyribonucleotides. It exists three classes of RNR. Class I RNR is a tetramer composed of the two types of subunits with stoichiometry α2β2 and three subunits have been identified in mammals : | ||
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M2 and p53R2 interact with M1 through the C-terminal binding domain. These two subunits share more than 80% sequence identity. But the few differences between the two are not unimportant, as it’s explained below. | M2 and p53R2 interact with M1 through the C-terminal binding domain. These two subunits share more than 80% sequence identity. But the few differences between the two are not unimportant, as it’s explained below. | ||
The first X-ray crystal structure of p53R2 has a resolution of 2,6 Å and permits to describe its structure and also to show the structural differences with the M2 subunit. | The first X-ray crystal structure of p53R2 has a resolution of 2,6 Å and permits to describe its structure and also to show the structural differences with the M2 subunit (Figure 1). | ||
=='''Structure and function'''== | =='''Structure and function'''== | ||
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<scene name='Sandbox156/Iron-binding_site/2'>An iron-binding site</scene> is highlighted. But concerning this site, the two monomers are not the same. Actually, the B monomer has two iron-binding site (called Fe2 and Fe1) whereas the A monomer has only one which is Fe2. This can be explained by structural changes in the helix that compose the two monomers. The 37 to 42 N-terminal residues (called the swivel loop) from one monomer can rotate between two conformations and can influence the position of the helix B or D on the opposite monomer. | <scene name='Sandbox156/Iron-binding_site/2'>An iron-binding site</scene> is highlighted. But concerning this site, the two monomers are not the same. Actually, the B monomer has two iron-binding site (called Fe2 and Fe1) whereas the A monomer has only one which is Fe2. This can be explained by structural changes in the helix that compose the two monomers. The 37 to 42 N-terminal residues (called the swivel loop) from one monomer can rotate between two conformations and can influence the position of the helix B or D on the opposite monomer. | ||
[[Image:Thetwomonomers.jpg|400px]] | [[Image:Thetwomonomers.jpg| thumb | center | 400px | Figure 1: The structure of the p53R2 protein is shown. P53R2 is built up by two monomers A and B, which contain several iron-binding sites.]] | ||
The N-terminal residues of the monomer A can stabilize the B helix of the monomer B due to different interactions. R41 of the monomer A forms a salt bridge with E119 of monomer A. This interaction permits the formation of a H-bond between R40 of monomer A with G101of monomer B. Furthermore K37 in monomer A forms a salt bridge with E105 of monomer B and this stabilize its B helix. All the interactions allow D100 of monomer B to be well oriented to bind Fe1 (see Figure | The N-terminal residues of the monomer A can stabilize the B helix of the monomer B due to different interactions. R41 of the monomer A forms a salt bridge with E119 of monomer A. This interaction permits the formation of a H-bond between R40 of monomer A with G101of monomer B. Furthermore K37 in monomer A forms a salt bridge with E105 of monomer B and this stabilize its B helix. All the interactions allow D100 of monomer B to be well oriented to bind Fe1 (see Figure 2, Smith P. et al., <ref>PMID:19728742</ref>). | ||
[[Image:Figure 1.jpg | thumb | Shown are the interactions between the N-terminal loop of monomer A and the continuous helix B of monomer B with the iron binding sites Fe1 and Fe2. | center]] | [[Image:Figure 1.jpg | thumb | Figure 2: Shown are the interactions between the N-terminal loop of monomer A and the continuous helix B of monomer B with the iron binding sites Fe1 and Fe2. | center]] | ||
On the contrary R40 of monomer B is bound to E119 of the same monomer and so it can not bind to G101 of the monomer A and the consequence is that F42 disturb the B helix of monomer A. D100 can not interact with Fe1. This explain why the monomer A has only one iron-binding site whereas the monomer B has two (see Figure | On the contrary R40 of monomer B is bound to E119 of the same monomer and so it can not bind to G101 of the monomer A and the consequence is that F42 disturb the B helix of monomer A. D100 can not interact with Fe1. This explain why the monomer A has only one iron-binding site whereas the monomer B has two (see Figure 3, Smith P. et al. <ref>PMID:19728742</ref>). | ||
[[Image:Figure 2.jpg | thumb | Shown are the interactions between the N-terminal loop of monomer B and the discontinuous helix B of monomer A with the iron binding site Fe2. | center]] | [[Image:Figure 2.jpg | thumb | Figure 3: Shown are the interactions between the N-terminal loop of monomer B and the discontinuous helix B of monomer A with the iron binding site Fe2. | center]] | ||
Compare to the M2 subunit, these iron-binding sites are less efficient. This is due to the different conformations that the p53R2 subunit can adopt (stabilization or not of the two helix B and D). | Compare to the M2 subunit, these iron-binding sites are less efficient. This is due to the different conformations that the p53R2 subunit can adopt (stabilization or not of the two helix B and D). | ||
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p53R2 is included in the RR class I which are characterized by a tyrosyl radical coupled with diiron cluster. A protein which possess tyrosyl radicals with binuclear center is known to have an oxidative or a reductive effect. So for the researchers Lijun Xue et al. <ref>PMID:16488986</ref> it raises the question of the redox properties of p53R2. They found that p53R2 is an antioxidant which can scavenge H2O2. The mitochondrial membrane is sensible to oxidative damage. H2O2 is a reactive oxygen specie (ROS) which can act on cellular growth and survival and is involved in pathogenesis like cancer. p53R2 prevents the loss of mitochondrial membrane by scavenging H2O2. This process protects cells by maintaining their genomic integrity and prevent from cancer. | p53R2 is included in the RR class I which are characterized by a tyrosyl radical coupled with diiron cluster. A protein which possess tyrosyl radicals with binuclear center is known to have an oxidative or a reductive effect. So for the researchers Lijun Xue et al. <ref>PMID:16488986</ref> it raises the question of the redox properties of p53R2. They found that p53R2 is an antioxidant which can scavenge H2O2. The mitochondrial membrane is sensible to oxidative damage. H2O2 is a reactive oxygen specie (ROS) which can act on cellular growth and survival and is involved in pathogenesis like cancer. p53R2 prevents the loss of mitochondrial membrane by scavenging H2O2. This process protects cells by maintaining their genomic integrity and prevent from cancer. | ||
==3D structures of ribonucleotide reductase== | |||
[[Ribonucleotide reductase]] | |||
==References== | |||
<references/> | |||
