MDM2

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{{STRUCTURE_2axi| PDB=2axi | SIZE=400| SCENE= |right|CAPTION=Human MDM2 (grey) complex with β-hairpin peptide (green), sulfate and morpholino-propane sulfonic acid [[1ycq]] }}
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<StructureSection load='2axi' size='350' side='right' scene='' caption='Human MDM2 (grey) complex with β-hairpin peptide (green), sulfate and morpholino-propane sulfonic acid [[1ycq]]'>
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==Function==
The '''MDM2''' or '''E3 ubiquitin-protein ligase MDM2''' oncoprotein is a cellular inhibitor of the [[P53|p53 tumor suppressor]] in that it can bind the transactivation domain of p53 and downregulate its ability to activate transcription. In certain [[Cancer|cancers]], MDM2 amplification is a common event and contributes to the inactivation of p53. The crystal structure of the 109-residue amino-terminal domain of MDM2 bound to 109-residue transactivation domain peptide of p53 revealed that MDM2 has a <scene name='Matt_Routh_sandbox/Hydrophobic_cavity/1'>deep hydrophobic cleft</scene> on which the p53 peptide binds as an amphipathic alpha helix. The interface relies on the steric complementarity between the MDM2 cleft and the hydrophobic face of the p53 alpha helix and, in particular, on a triad of p53 amino acids-Phe19, Trp23, and Leu26-which insert <scene name='Matt_Routh_sandbox/Connection_to_p53/5'>deep inside</scene> the MDM2 cleft. These same p53 residues are also involved in transactivation, supporting the hypothesis that MDM2 inactivates p53 by concealing its transactivation domain. The structure also suggests that the amphipathic alpha helix may be a common structural motif in the binding of a diverse family of transactivation factors to the TATA-binding protein-associated factors.<ref name="Kussie">PMID:8875929</ref>
The '''MDM2''' or '''E3 ubiquitin-protein ligase MDM2''' oncoprotein is a cellular inhibitor of the [[P53|p53 tumor suppressor]] in that it can bind the transactivation domain of p53 and downregulate its ability to activate transcription. In certain [[Cancer|cancers]], MDM2 amplification is a common event and contributes to the inactivation of p53. The crystal structure of the 109-residue amino-terminal domain of MDM2 bound to 109-residue transactivation domain peptide of p53 revealed that MDM2 has a <scene name='Matt_Routh_sandbox/Hydrophobic_cavity/1'>deep hydrophobic cleft</scene> on which the p53 peptide binds as an amphipathic alpha helix. The interface relies on the steric complementarity between the MDM2 cleft and the hydrophobic face of the p53 alpha helix and, in particular, on a triad of p53 amino acids-Phe19, Trp23, and Leu26-which insert <scene name='Matt_Routh_sandbox/Connection_to_p53/5'>deep inside</scene> the MDM2 cleft. These same p53 residues are also involved in transactivation, supporting the hypothesis that MDM2 inactivates p53 by concealing its transactivation domain. The structure also suggests that the amphipathic alpha helix may be a common structural motif in the binding of a diverse family of transactivation factors to the TATA-binding protein-associated factors.<ref name="Kussie">PMID:8875929</ref>
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==3D structures of MDM2==
==3D structures of MDM2==
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[[MDM2 3D structures]]
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Updated on {{REVISIONDAY2}}-{{MONTHNAME|{{REVISIONMONTH}}}}-{{REVISIONYEAR}}
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</StructureSection>
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{{#tree:id=OrganizedByTopic|openlevels=0|
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*'''MDM2'''
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**[[4ipf]], [[4j74]] – fMDM2 p53-binding domain (mutant) - frog<br />
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**[[1z1m]] – hMDM2 N terminal – human - NMR<br />
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**[[2c6a]], [[2c6b]], [[2cr8]] – hMDM2 C4 Zinc-finger domain – NMR<br />
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**[[2hdp]] - hMDM2 C4 ring-finger domain – NMR<br />
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*MDM2 complex with small molecule
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**[[1rv1]], [[1t4e]], [[3lbk]], [[4dij]], [[3vzv]], [[3w69]], [[3lkb]], [[4lwt]], [[4lwu]], [[4lwv]], [[4oq3]] – hMDM2 (mutant) p53-binding domain + inhibitor<br />
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**[[3jzk]], [[3lbl]], [[3tu1]], [[4ere]], [[4erf]], [[3tj2]], [[4hbm]], [[4jv7]], [[4jv9]], [[4jve]], [[4jvr]], [[4jwr]], [[4mdn]], [[4mdq]], [[4oas]], [[4oba]], [[4occ]], [[4ode]], [[4odf]], [[4ogn]], [[4ogt]], [[4ogv]], [[4qo4]], [[4hg7]], [[4wt2]] - hMDM2 p53-binding domain + inhibitor<br />
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**[[2lzg]] - hMDM2 p53-binding domain + inhibitor – NMR<br />
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**[[3vbg]] - hMDM2 p53-binding domain + indolyl hydantoin<br />
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**[[1ttv]] - fMDM2 (mutant) p53-binding domain + inhibitor – NMR
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**[[4j3e]], [[4j7d]], [[4j7e]], [[4jrg]], [[4jsc]] - fMDM2 p53-binding domain (mutant) + inhibitor<br />
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*MDM2 complex with peptide
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**[[1ycq]], [[1ycr]] – fMDM2 + p53 peptide <br />
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**[[1t4f]], [[4hfz]] - hMDM2 (mutant) p53-binding domain + p53 peptide<br />
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**[[3v3b]] - hMDM2 p53-binding domain + p53 peptide<br />
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**[[3jzr]] - hMDM2 p53-binding domain + pDI6W peptide<br />
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**[[4umn]] - hMDM2 p53-binding domain + M06 peptide<br />
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**[[3jzs]] - hMDM2 p53-binding domain + pDIQ peptide<br />
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**[[3tpx]] - hMDM2 p53-binding domain + D-peptide inhibitor<br />
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**[[2axi]], [[2gv2]], [[3eqs]], [[3g03]], [[3iux]], [[3lnj]], [[3lnz]], [[3iwy]] - hMDM2 p53-binding domain + peptide<br />
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**[[2m86]] - hMDM2 p53-binding domain + cyclotide - NMR<br />
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**[[2vje]], [[2vjf]] - hMDM2 ring domain + MDM4 peptide<br />
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}}
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==Additional Resources==
==Additional Resources==

Current revision

Human MDM2 (grey) complex with β-hairpin peptide (green), sulfate and morpholino-propane sulfonic acid 1ycq

Drag the structure with the mouse to rotate

Additional Resources

For additional information, see: Cancer

Reference

  1. ↑ Kussie PH, Gorina S, Marechal V, Elenbaas B, Moreau J, Levine AJ, Pavletich NP. Structure of the MDM2 oncoprotein bound to the p53 tumor suppressor transactivation domain. Science. 1996 Nov 8;274(5289):948-53. PMID:8875929
  2. ↑ 2.0 2.1 2.2 Pollock RE, Lang A, El-Naggar AK, Radinsky R, Hung MC. Enhanced MDM2 Oncoprotein Expression in Soft Tissue Sarcoma: Several Possible Regulatory Mechanisms. Sarcoma. 1997;1(1):23-9. PMID:18521197 doi:10.1080/13577149778443
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