4xxb: Difference between revisions

Revision as of 17:56, 26 April 2023

Crystal structure of human MDM2-RPL11

Structural highlights

4xxb is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	BME, IMD, ZN
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

RL11_HUMAN Blackfan-Diamond disease. Diamond-Blackfan anemia 7 (DBA7) [MIM:612562: A form of Diamond-Blackfan anemia, a congenital non-regenerative hypoplastic anemia that usually presents early in infancy. Diamond-Blackfan anemia is characterized by a moderate to severe macrocytic anemia, erythroblastopenia, and an increased risk of malignancy. 30 to 40% of Diamond-Blackfan anemia patients present with short stature and congenital anomalies, the most frequent being craniofacial (Pierre-Robin syndrome and cleft palate), thumb and urogenital anomalies. Note=The disease is caused by mutations affecting the gene represented in this entry.^[1] ^[2]

Function

RL11_HUMAN Binds to 5S ribosomal RNA (By similarity). Required for rRNA maturation and formation of the 60S ribosomal subunits. Promotes nucleolar location of PML (By similarity).^[3]

Publication Abstract from PubMed

The central region of MDM2 is critical for p53 activation and tumor suppression. Upon ribosomal stress, this region is bound by ribosomal proteins, particularly ribosomal protein L11 (RPL11), leading to MDM2 inactivation and subsequent p53 activation. Here, we solved the complex structure of human MDM2-RPL11 at 2.4 A. MDM2 extensively interacts with RPL11 through an acidic domain and two zinc fingers. Formation of the MDM2-RPL11 complex induces substantial conformational changes in both proteins. RPL11, unable to bind MDM2 mutants, fails to induce the activation of p53 in cells. MDM2 mimics 28S rRNA binding to RPL11. The C4 zinc finger determines RPL11 binding to MDM2 but not its homolog, MDMX. Our results highlight the essential role of the RPL11-MDM2 interaction in p53 activation and tumor suppression and provide a structural basis for potential new anti-tumor drug development.

Structure of human MDM2 complexed with RPL11 reveals the molecular basis of p53 activation.,Zheng J, Lang Y, Zhang Q, Cui D, Sun H, Jiang L, Chen Z, Zhang R, Gao Y, Tian W, Wu W, Tang J, Chen Z Genes Dev. 2015 Jul 15;29(14):1524-34. doi: 10.1101/gad.261792.115. PMID:26220995^[4]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Gazda HT, Sheen MR, Vlachos A, Choesmel V, O'Donohue MF, Schneider H, Darras N, Hasman C, Sieff CA, Newburger PE, Ball SE, Niewiadomska E, Matysiak M, Zaucha JM, Glader B, Niemeyer C, Meerpohl JJ, Atsidaftos E, Lipton JM, Gleizes PE, Beggs AH. Ribosomal protein L5 and L11 mutations are associated with cleft palate and abnormal thumbs in Diamond-Blackfan anemia patients. Am J Hum Genet. 2008 Dec;83(6):769-80. PMID:19061985 doi:S0002-9297(08)00589-2
↑ Cmejla R, Cmejlova J, Handrkova H, Petrak J, Petrtylova K, Mihal V, Stary J, Cerna Z, Jabali Y, Pospisilova D. Identification of mutations in the ribosomal protein L5 (RPL5) and ribosomal protein L11 (RPL11) genes in Czech patients with Diamond-Blackfan anemia. Hum Mutat. 2009 Mar;30(3):321-7. doi: 10.1002/humu.20874. PMID:19191325 doi:10.1002/humu.20874
↑ Gazda HT, Sheen MR, Vlachos A, Choesmel V, O'Donohue MF, Schneider H, Darras N, Hasman C, Sieff CA, Newburger PE, Ball SE, Niewiadomska E, Matysiak M, Zaucha JM, Glader B, Niemeyer C, Meerpohl JJ, Atsidaftos E, Lipton JM, Gleizes PE, Beggs AH. Ribosomal protein L5 and L11 mutations are associated with cleft palate and abnormal thumbs in Diamond-Blackfan anemia patients. Am J Hum Genet. 2008 Dec;83(6):769-80. PMID:19061985 doi:S0002-9297(08)00589-2
↑ Zheng J, Lang Y, Zhang Q, Cui D, Sun H, Jiang L, Chen Z, Zhang R, Gao Y, Tian W, Wu W, Tang J, Chen Z. Structure of human MDM2 complexed with RPL11 reveals the molecular basis of p53 activation. Genes Dev. 2015 Jul 15;29(14):1524-34. doi: 10.1101/gad.261792.115. PMID:26220995 doi:https://dx.doi.org/10.1101/gad.261792.115

Proteopedia Page Contributors and Editors (what is this?)

OCA

[1] Gazda HT, Sheen MR, Vlachos A, Choesmel V, O'Donohue MF, Schneider H, Darras N, Hasman C, Sieff CA, Newburger PE, Ball SE, Niewiadomska E, Matysiak M, Zaucha JM, Glader B, Niemeyer C, Meerpohl JJ, Atsidaftos E, Lipton JM, Gleizes PE, Beggs AH. Ribosomal protein L5 and L11 mutations are associated with cleft palate and abnormal thumbs in Diamond-Blackfan anemia patients. Am J Hum Genet. 2008 Dec;83(6):769-80. PMID:19061985 doi:S0002-9297(08)00589-2

[2] Cmejla R, Cmejlova J, Handrkova H, Petrak J, Petrtylova K, Mihal V, Stary J, Cerna Z, Jabali Y, Pospisilova D. Identification of mutations in the ribosomal protein L5 (RPL5) and ribosomal protein L11 (RPL11) genes in Czech patients with Diamond-Blackfan anemia. Hum Mutat. 2009 Mar;30(3):321-7. doi: 10.1002/humu.20874. PMID:19191325 doi:10.1002/humu.20874

[3] Gazda HT, Sheen MR, Vlachos A, Choesmel V, O'Donohue MF, Schneider H, Darras N, Hasman C, Sieff CA, Newburger PE, Ball SE, Niewiadomska E, Matysiak M, Zaucha JM, Glader B, Niemeyer C, Meerpohl JJ, Atsidaftos E, Lipton JM, Gleizes PE, Beggs AH. Ribosomal protein L5 and L11 mutations are associated with cleft palate and abnormal thumbs in Diamond-Blackfan anemia patients. Am J Hum Genet. 2008 Dec;83(6):769-80. PMID:19061985 doi:S0002-9297(08)00589-2

[4] Zheng J, Lang Y, Zhang Q, Cui D, Sun H, Jiang L, Chen Z, Zhang R, Gao Y, Tian W, Wu W, Tang J, Chen Z. Structure of human MDM2 complexed with RPL11 reveals the molecular basis of p53 activation. Genes Dev. 2015 Jul 15;29(14):1524-34. doi: 10.1101/gad.261792.115. PMID:26220995 doi:https://dx.doi.org/10.1101/gad.261792.115

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[2]

[3]

[4]

@@ Line 3: / Line 3: @@
 <StructureSection load='4xxb' size='340' side='right'caption='[[4xxb]], [[Resolution|resolution]] 2.40&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[4xxb]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4XXB OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4XXB FirstGlance]. <br>
+<table><tr><td colspan='2'>[[4xxb]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4XXB OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4XXB FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=BME:BETA-MERCAPTOETHANOL'>BME</scene>, <scene name='pdbligand=IMD:IMIDAZOLE'>IMD</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
+</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=BME:BETA-MERCAPTOETHANOL'>BME</scene>, <scene name='pdbligand=IMD:IMIDAZOLE'>IMD</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
-<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">RPL11 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN]), MDM2 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4xxb FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4xxb OCA], [https://pdbe.org/4xxb PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4xxb RCSB], [https://www.ebi.ac.uk/pdbsum/4xxb PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4xxb ProSAT]</span></td></tr>
-<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4xxb FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4xxb OCA], [http://pdbe.org/4xxb PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4xxb RCSB], [http://www.ebi.ac.uk/pdbsum/4xxb PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4xxb ProSAT]</span></td></tr>
 </table>
 == Disease ==
-[[http://www.uniprot.org/uniprot/RL11_HUMAN RL11_HUMAN]] Blackfan-Diamond disease. Diamond-Blackfan anemia 7 (DBA7) [MIM:[http://omim.org/entry/612562 612562]]: A form of Diamond-Blackfan anemia, a congenital non-regenerative hypoplastic anemia that usually presents early in infancy. Diamond-Blackfan anemia is characterized by a moderate to severe macrocytic anemia, erythroblastopenia, and an increased risk of malignancy. 30 to 40% of Diamond-Blackfan anemia patients present with short stature and congenital anomalies, the most frequent being craniofacial (Pierre-Robin syndrome and cleft palate), thumb and urogenital anomalies. Note=The disease is caused by mutations affecting the gene represented in this entry.<ref>PMID:19061985</ref> <ref>PMID:19191325</ref>  [[http://www.uniprot.org/uniprot/MDM2_HUMAN MDM2_HUMAN]] Note=Seems to be amplified in certain tumors (including soft tissue sarcomas, osteosarcomas and gliomas). A higher frequency of splice variants lacking p53 binding domain sequences was found in late-stage and high-grade ovarian and bladder carcinomas. Four of the splice variants show loss of p53 binding.
+[https://www.uniprot.org/uniprot/RL11_HUMAN RL11_HUMAN] Blackfan-Diamond disease. Diamond-Blackfan anemia 7 (DBA7) [MIM:[https://omim.org/entry/612562 612562]: A form of Diamond-Blackfan anemia, a congenital non-regenerative hypoplastic anemia that usually presents early in infancy. Diamond-Blackfan anemia is characterized by a moderate to severe macrocytic anemia, erythroblastopenia, and an increased risk of malignancy. 30 to 40% of Diamond-Blackfan anemia patients present with short stature and congenital anomalies, the most frequent being craniofacial (Pierre-Robin syndrome and cleft palate), thumb and urogenital anomalies. Note=The disease is caused by mutations affecting the gene represented in this entry.<ref>PMID:19061985</ref> <ref>PMID:19191325</ref>
 == Function ==
-[[http://www.uniprot.org/uniprot/RL11_HUMAN RL11_HUMAN]] Binds to 5S ribosomal RNA (By similarity). Required for rRNA maturation and formation of the 60S ribosomal subunits. Promotes nucleolar location of PML (By similarity).<ref>PMID:19061985</ref>  [[http://www.uniprot.org/uniprot/MDM2_HUMAN MDM2_HUMAN]] E3 ubiquitin-protein ligase that mediates ubiquitination of p53/TP53, leading to its degradation by the proteasome. Inhibits p53/TP53- and p73/TP73-mediated cell cycle arrest and apoptosis by binding its transcriptional activation domain. Also acts as an ubiquitin ligase E3 toward itself and ARRB1. Permits the nuclear export of p53/TP53. Promotes proteasome-dependent ubiquitin-independent degradation of retinoblastoma RB1 protein. Inhibits DAXX-mediated apoptosis by inducing its ubiquitination and degradation. Component of the TRIM28/KAP1-MDM2-p53/TP53 complex involved in stabilizing p53/TP53. Also component of the TRIM28/KAP1-ERBB4-MDM2 complex which links growth factor and DNA damage response pathways. Mediates ubiquitination and subsequent proteasome degradation of DYRK2 in nucleus. Ubiquitinates IGF1R and promotes it to proteasomal degradation.<ref>PMID:12821780</ref> <ref>PMID:15053880</ref> <ref>PMID:15195100</ref> <ref>PMID:16337594</ref> <ref>PMID:15632057</ref> <ref>PMID:17290220</ref> <ref>PMID:19098711</ref> <ref>PMID:19219073</ref> <ref>PMID:19965871</ref> <ref>PMID:20858735</ref> <ref>PMID:20173098</ref>
+[https://www.uniprot.org/uniprot/RL11_HUMAN RL11_HUMAN] Binds to 5S ribosomal RNA (By similarity). Required for rRNA maturation and formation of the 60S ribosomal subunits. Promotes nucleolar location of PML (By similarity).<ref>PMID:19061985</ref>
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
@@ Line 23: / Line 22: @@
 ==See Also==
-*[[Ribosomal protein L11|Ribosomal protein L11]]
+*[[Ribosomal protein L11 3D structures|Ribosomal protein L11 3D structures]]
 == References ==
 <references/>
 __TOC__
 </StructureSection>
-[[Category: Human]]
+[[Category: Homo sapiens]]
 [[Category: Large Structures]]
-[[Category: Chen, Z]]
+[[Category: Chen Z]]
-[[Category: Zheng, J]]
+[[Category: Zheng J]]
-[[Category: Mdm2]]
-[[Category: Modpipe model of up]]
-[[Category: Rna binding protein-metal binding protein complex]]
-[[Category: Rpl11]]

4xxb: Difference between revisions

Revision as of 17:56, 26 April 2023

Crystal structure of human MDM2-RPL11

Structural highlights

Disease

Function

Publication Abstract from PubMed

See Also

References

Contents

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