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| | ==FKBP MUTANT F36V COMPLEXED WITH REMODELED SYNTHETIC LIGAND== | | ==FKBP MUTANT F36V COMPLEXED WITH REMODELED SYNTHETIC LIGAND== |
| - | <StructureSection load='1bl4' size='340' side='right' caption='[[1bl4]], [[Resolution|resolution]] 1.90Å' scene=''> | + | <StructureSection load='1bl4' size='340' side='right'caption='[[1bl4]], [[Resolution|resolution]] 1.90Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[1bl4]] 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=1BL4 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1BL4 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[1bl4]] 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=1BL4 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1BL4 FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=AP1:{3-[3-(3,4-DIMETHOXY-PHENYL)-1-(1-{1-[2-(3,4,5-TRIMETHOXY-PHENYL)-BUTYRYL]-PIPERIDIN-2YL}-VINYLOXY)-PROPYL]-PHENOXY}-ACETIC+ACID'>AP1</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]] 1.9Å</td></tr> |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Peptidylprolyl_isomerase Peptidylprolyl isomerase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=5.2.1.8 5.2.1.8] </span></td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=AP1:{3-[3-(3,4-DIMETHOXY-PHENYL)-1-(1-{1-[2-(3,4,5-TRIMETHOXY-PHENYL)-BUTYRYL]-PIPERIDIN-2YL}-VINYLOXY)-PROPYL]-PHENOXY}-ACETIC+ACID'>AP1</scene></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=1bl4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1bl4 OCA], [http://pdbe.org/1bl4 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=1bl4 RCSB], [http://www.ebi.ac.uk/pdbsum/1bl4 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=1bl4 ProSAT]</span></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=1bl4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1bl4 OCA], [https://pdbe.org/1bl4 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1bl4 RCSB], [https://www.ebi.ac.uk/pdbsum/1bl4 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1bl4 ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/FKB1A_HUMAN FKB1A_HUMAN]] Keeps in an inactive conformation TGFBR1, the TGF-beta type I serine/threonine kinase receptor, preventing TGF-beta receptor activation in absence of ligand. Recruites SMAD7 to ACVR1B which prevents the association of SMAD2 and SMAD3 with the activin receptor complex, thereby blocking the activin signal. May modulate the RYR1 calcium channel activity. PPIases accelerate the folding of proteins. It catalyzes the cis-trans isomerization of proline imidic peptide bonds in oligopeptides.<ref>PMID:9233797</ref> <ref>PMID:16720724</ref> | + | [https://www.uniprot.org/uniprot/FKB1A_HUMAN FKB1A_HUMAN] Keeps in an inactive conformation TGFBR1, the TGF-beta type I serine/threonine kinase receptor, preventing TGF-beta receptor activation in absence of ligand. Recruites SMAD7 to ACVR1B which prevents the association of SMAD2 and SMAD3 with the activin receptor complex, thereby blocking the activin signal. May modulate the RYR1 calcium channel activity. PPIases accelerate the folding of proteins. It catalyzes the cis-trans isomerization of proline imidic peptide bonds in oligopeptides.<ref>PMID:9233797</ref> <ref>PMID:16720724</ref> |
| | == Evolutionary Conservation == | | == Evolutionary Conservation == |
| | [[Image:Consurf_key_small.gif|200px|right]] | | [[Image:Consurf_key_small.gif|200px|right]] |
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| | ==See Also== | | ==See Also== |
| - | *[[FK506 binding protein|FK506 binding protein]] | + | *[[FKBP 3D structures|FKBP 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Peptidylprolyl isomerase]] | + | [[Category: Large Structures]] |
| - | [[Category: Amara, J]] | + | [[Category: Amara J]] |
| - | [[Category: Clackson, T]] | + | [[Category: Cerasoli Junior F]] |
| - | [[Category: Courage, N L]] | + | [[Category: Clackson T]] |
| - | [[Category: Gilman, M]] | + | [[Category: Courage NL]] |
| - | [[Category: Hatada, M H]] | + | [[Category: Gilman M]] |
| - | [[Category: Holt, D]] | + | [[Category: Hatada MH]] |
| - | [[Category: Junior, F Cerasoli]]
| + | [[Category: Holt D]] |
| - | [[Category: Lu, X]] | + | [[Category: Lu X]] |
| - | [[Category: Magari, S R]] | + | [[Category: Magari SR]] |
| - | [[Category: Rollins, C T]] | + | [[Category: Rollins CT]] |
| - | [[Category: Rozamus, L W]] | + | [[Category: Rozamus LW]] |
| - | [[Category: Stevenson, L F]] | + | [[Category: Stevenson LF]] |
| - | [[Category: Wood, S A]] | + | [[Category: Wood SA]] |
| - | [[Category: Yang, W]] | + | [[Category: Yang W]] |
| - | [[Category: Isomerase]]
| + | |
| - | [[Category: Rotamase]]
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| Structural highlights
Function
FKB1A_HUMAN Keeps in an inactive conformation TGFBR1, the TGF-beta type I serine/threonine kinase receptor, preventing TGF-beta receptor activation in absence of ligand. Recruites SMAD7 to ACVR1B which prevents the association of SMAD2 and SMAD3 with the activin receptor complex, thereby blocking the activin signal. May modulate the RYR1 calcium channel activity. PPIases accelerate the folding of proteins. It catalyzes the cis-trans isomerization of proline imidic peptide bonds in oligopeptides.[1] [2]
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
FKBP ligand homodimers can be used to activate signaling events inside cells and animals that have been engineered to express fusions between appropriate signaling domains and FKBP. However, use of these dimerizers in vivo is potentially limited by ligand binding to endogenous FKBP. We have designed ligands that bind specifically to a mutated FKBP over the wild-type protein by remodeling an FKBP-ligand interface to introduce a specificity binding pocket. A compound bearing an ethyl substituent in place of a carbonyl group exhibited sub-nanomolar affinity and 1,000-fold selectivity for a mutant FKBP with a compensating truncation of a phenylalanine residue. Structural and functional analysis of the new pocket showed that recognition is surprisingly relaxed, with the modified ligand only partially filling the engineered cavity. We incorporated the specificity pocket into a fusion protein containing FKBP and the intracellular domain of the Fas receptor. Cells expressing this modified chimeric protein potently underwent apoptosis in response to AP1903, a homodimer of the modified ligand, both in culture and when implanted into mice. Remodeled dimerizers such as AP1903 are ideal reagents for controlling the activities of cells that have been modified by gene therapy procedures, without interference from endogenous FKBP.
Redesigning an FKBP-ligand interface to generate chemical dimerizers with novel specificity.,Clackson T, Yang W, Rozamus LW, Hatada M, Amara JF, Rollins CT, Stevenson LF, Magari SR, Wood SA, Courage NL, Lu X, Cerasoli F Jr, Gilman M, Holt DA Proc Natl Acad Sci U S A. 1998 Sep 1;95(18):10437-42. PMID:9724721[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Chen YG, Liu F, Massague J. Mechanism of TGFbeta receptor inhibition by FKBP12. EMBO J. 1997 Jul 1;16(13):3866-76. PMID:9233797 doi:10.1093/emboj/16.13.3866
- ↑ Yamaguchi T, Kurisaki A, Yamakawa N, Minakuchi K, Sugino H. FKBP12 functions as an adaptor of the Smad7-Smurf1 complex on activin type I receptor. J Mol Endocrinol. 2006 Jun;36(3):569-79. PMID:16720724 doi:10.1677/jme.1.01966
- ↑ Clackson T, Yang W, Rozamus LW, Hatada M, Amara JF, Rollins CT, Stevenson LF, Magari SR, Wood SA, Courage NL, Lu X, Cerasoli F Jr, Gilman M, Holt DA. Redesigning an FKBP-ligand interface to generate chemical dimerizers with novel specificity. Proc Natl Acad Sci U S A. 1998 Sep 1;95(18):10437-42. PMID:9724721
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