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| | ==X-ray crystallographic structure of a high affinity IGF2 antagonist (Domain11 AB5 RHH) based on human IGF2R domain 11== | | ==X-ray crystallographic structure of a high affinity IGF2 antagonist (Domain11 AB5 RHH) based on human IGF2R domain 11== |
| - | <StructureSection load='5iei' size='340' side='right' caption='[[5iei]], [[Resolution|resolution]] 2.80Å' scene=''> | + | <StructureSection load='5iei' size='340' side='right'caption='[[5iei]], [[Resolution|resolution]] 2.80Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5iei]] is a 1 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=5IEI OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5IEI FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5iei]] is a 1 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=5IEI OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5IEI FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.8Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1gp0|1gp0]], [[2l2a|2l2a]], [[2l29|2l29]], [[2m68|2m68]], [[2m6t|2m6t]]</td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">IGF2R, MPRI ([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=5iei FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5iei OCA], [https://pdbe.org/5iei PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5iei RCSB], [https://www.ebi.ac.uk/pdbsum/5iei PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5iei 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=5iei FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5iei OCA], [http://pdbe.org/5iei PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5iei RCSB], [http://www.ebi.ac.uk/pdbsum/5iei PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5iei ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/MPRI_HUMAN MPRI_HUMAN]] Transport of phosphorylated lysosomal enzymes from the Golgi complex and the cell surface to lysosomes. Lysosomal enzymes bearing phosphomannosyl residues bind specifically to mannose-6-phosphate receptors in the Golgi apparatus and the resulting receptor-ligand complex is transported to an acidic prelyosomal compartment where the low pH mediates the dissociation of the complex. This receptor also binds IGF2. Acts as a positive regulator of T-cell coactivation, by binding DPP4.<ref>PMID:10900005</ref> | + | [https://www.uniprot.org/uniprot/MPRI_HUMAN MPRI_HUMAN] Transport of phosphorylated lysosomal enzymes from the Golgi complex and the cell surface to lysosomes. Lysosomal enzymes bearing phosphomannosyl residues bind specifically to mannose-6-phosphate receptors in the Golgi apparatus and the resulting receptor-ligand complex is transported to an acidic prelyosomal compartment where the low pH mediates the dissociation of the complex. This receptor also binds IGF2. Acts as a positive regulator of T-cell coactivation, by binding DPP4.<ref>PMID:10900005</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Crump, M P]] | + | [[Category: Large Structures]] |
| - | [[Category: Frago, S]] | + | [[Category: Crump MP]] |
| - | [[Category: Hassan, A B]] | + | [[Category: Frago S]] |
| - | [[Category: Nicholls, R D]] | + | [[Category: Hassan AB]] |
| - | [[Category: Strickland, M]] | + | [[Category: Nicholls RD]] |
| - | [[Category: Williams, C]] | + | [[Category: Strickland M]] |
| - | [[Category: Domain 11]]
| + | [[Category: Williams C]] |
| - | [[Category: Igf2]]
| + | |
| - | [[Category: Igf2r]]
| + | |
| - | [[Category: Transport protein]]
| + | |
| Structural highlights
Function
MPRI_HUMAN Transport of phosphorylated lysosomal enzymes from the Golgi complex and the cell surface to lysosomes. Lysosomal enzymes bearing phosphomannosyl residues bind specifically to mannose-6-phosphate receptors in the Golgi apparatus and the resulting receptor-ligand complex is transported to an acidic prelyosomal compartment where the low pH mediates the dissociation of the complex. This receptor also binds IGF2. Acts as a positive regulator of T-cell coactivation, by binding DPP4.[1]
Publication Abstract from PubMed
Among the 15 extracellular domains of the mannose 6-phosphate/insulin-like growth factor-2 receptor (M6P/IGF2R), domain 11 has evolved a binding site for IGF2 to negatively regulate ligand bioavailability and mammalian growth. Despite the highly evolved structural loops of the IGF2:domain 11 binding site, affinity-enhancing AB loop mutations suggest that binding is modifiable. Here we examine the extent to which IGF2:domain 11 affinity, and its specificity over IGF1, can be enhanced, and we examine the structural basis of the mechanistic and functional consequences. Domain 11 binding loop mutants were selected by yeast surface display combined with high-resolution structure-based predictions, and validated by surface plasmon resonance. We discovered previously unidentified mutations in the ligand-interacting surface binding loops (AB, CD, FG, and HI). Five combined mutations increased rigidity of the AB loop, as confirmed by NMR. When added to three independently identified CD and FG loop mutations that reduced the koff value by twofold, these mutations resulted in an overall selective 100-fold improvement in affinity. The structural basis of the evolved affinity was improved shape complementarity established by interloop (AB-CD) and intraloop (FG-FG) side chain interactions. The high affinity of the combinatorial domain 11 Fc fusion proteins functioned as ligand-soluble antagonists or traps that depleted pathological IGF2 isoforms from serum and abrogated IGF2-dependent signaling in vivo. An evolved and reengineered high-specificity M6P/IGF2R domain 11 binding site for IGF2 may improve therapeutic targeting of the frequent IGF2 gain of function observed in human cancer.
Functional evolution of IGF2:IGF2R domain 11 binding generates novel structural interactions and a specific IGF2 antagonist.,Frago S, Nicholls RD, Strickland M, Hughes J, Williams C, Garner L, Surakhy M, Maclean R, Rezgui D, Prince SN, Zaccheo OJ, Ebner D, Sanegre S, Yu S, Buffa FM, Crump MP, Hassan AB Proc Natl Acad Sci U S A. 2016 May 17;113(20):E2766-75. doi:, 10.1073/pnas.1513023113. Epub 2016 May 2. PMID:27140600[2]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Ikushima H, Munakata Y, Ishii T, Iwata S, Terashima M, Tanaka H, Schlossman SF, Morimoto C. Internalization of CD26 by mannose 6-phosphate/insulin-like growth factor II receptor contributes to T cell activation. Proc Natl Acad Sci U S A. 2000 Jul 18;97(15):8439-44. PMID:10900005
- ↑ Frago S, Nicholls RD, Strickland M, Hughes J, Williams C, Garner L, Surakhy M, Maclean R, Rezgui D, Prince SN, Zaccheo OJ, Ebner D, Sanegre S, Yu S, Buffa FM, Crump MP, Hassan AB. Functional evolution of IGF2:IGF2R domain 11 binding generates novel structural interactions and a specific IGF2 antagonist. Proc Natl Acad Sci U S A. 2016 May 17;113(20):E2766-75. doi:, 10.1073/pnas.1513023113. Epub 2016 May 2. PMID:27140600 doi:http://dx.doi.org/10.1073/pnas.1513023113
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