6tu9

From Proteopedia

(Difference between revisions)

Current revision

The ROR1 Pseudokinase Domain Bound To Ponatinib

Structural highlights

6tu9 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.
Method:	X-ray diffraction, Resolution 1.94Å
Ligands:
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

ROR1_HUMAN The disease is caused by mutations affecting the gene represented in this entry.

Function

ROR1_HUMAN Has very low kinase activity in vitro and is unlikely to function as a tyrosine kinase in vivo (PubMed:25029443). Receptor for ligand WNT5A which activate downstream NFkB signaling pathway and may result in the inhibition of WNT3A-mediated signaling (PubMed:25029443, PubMed:27162350). In inner ear, crucial for spiral ganglion neurons to innervate auditory hair cells (PubMed:27162350).^[1] ^[2]

Publication Abstract from PubMed

Despite their apparent lack of catalytic activity, pseudokinases are essential signaling molecules. Here, we describe the structural and dynamic properties of pseudokinase domains from the Wnt-binding receptor tyrosine kinases (PTK7, ROR1, ROR2, and RYK), which play important roles in development. We determined structures of all pseudokinase domains in this family and found that they share a conserved inactive conformation in their activation loop that resembles the autoinhibited insulin receptor kinase (IRK). They also have inaccessible ATP-binding pockets, occluded by aromatic residues that mimic a cofactor-bound state. Structural comparisons revealed significant domain plasticity and alternative interactions that substitute for absent conserved motifs. The pseudokinases also showed dynamic properties that were strikingly similar to those of IRK. Despite the inaccessible ATP site, screening identified ATP-competitive type-II inhibitors for ROR1. Our results set the stage for an emerging therapeutic modality of "conformational disruptors" to inhibit or modulate non-catalytic functions of pseudokinases deregulated in disease.

Structural Insights into Pseudokinase Domains of Receptor Tyrosine Kinases.,Sheetz JB, Mathea S, Karvonen H, Malhotra K, Chatterjee D, Niininen W, Perttila R, Preuss F, Suresh K, Stayrook SE, Tsutsui Y, Radhakrishnan R, Ungureanu D, Knapp S, Lemmon MA Mol Cell. 2020 Jun 24. pii: S1097-2765(20)30420-2. doi:, 10.1016/j.molcel.2020.06.018. PMID:32619402^[3]

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

References

↑ Bainbridge TW, DeAlmeida VI, Izrael-Tomasevic A, Chalouni C, Pan B, Goldsmith J, Schoen AP, Quinones GA, Kelly R, Lill JR, Sandoval W, Costa M, Polakis P, Arnott D, Rubinfeld B, Ernst JA. Evolutionary divergence in the catalytic activity of the CAM-1, ROR1 and ROR2 kinase domains. PLoS One. 2014 Jul 16;9(7):e102695. doi: 10.1371/journal.pone.0102695., eCollection 2014. PMID:25029443 doi:http://dx.doi.org/10.1371/journal.pone.0102695
↑ Diaz-Horta O, Abad C, Sennaroglu L, Foster J 2nd, DeSmidt A, Bademci G, Tokgoz-Yilmaz S, Duman D, Cengiz FB, Grati M, Fitoz S, Liu XZ, Farooq A, Imtiaz F, Currall BB, Morton CC, Nishita M, Minami Y, Lu Z, Walz K, Tekin M. ROR1 is essential for proper innervation of auditory hair cells and hearing in humans and mice. Proc Natl Acad Sci U S A. 2016 May 24;113(21):5993-8. doi:, 10.1073/pnas.1522512113. Epub 2016 May 9. PMID:27162350 doi:http://dx.doi.org/10.1073/pnas.1522512113
↑ Sheetz JB, Mathea S, Karvonen H, Malhotra K, Chatterjee D, Niininen W, Perttila R, Preuss F, Suresh K, Stayrook SE, Tsutsui Y, Radhakrishnan R, Ungureanu D, Knapp S, Lemmon MA. Structural Insights into Pseudokinase Domains of Receptor Tyrosine Kinases. Mol Cell. 2020 Jun 24. pii: S1097-2765(20)30420-2. doi:, 10.1016/j.molcel.2020.06.018. PMID:32619402 doi:http://dx.doi.org/10.1016/j.molcel.2020.06.018

1 Structural highlights
2 Disease
3 Function
4 Publication Abstract from PubMed
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/6tu9"

@@ Line 3: / Line 3: @@
 <StructureSection load='6tu9' size='340' side='right'caption='[[6tu9]], [[Resolution|resolution]] 1.94&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[6tu9]] 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=6TU9 OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6TU9 FirstGlance]. <br>
+<table><tr><td colspan='2'>[[6tu9]] 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=6TU9 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6TU9 FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=0LI:3-(IMIDAZO[1,2-B]PYRIDAZIN-3-YLETHYNYL)-4-METHYL-N-{4-[(4-METHYLPIPERAZIN-1-YL)METHYL]-3-(TRIFLUOROMETHYL)PHENYL}BENZAMIDE'>0LI</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]] 1.94&#8491;</td></tr>
-<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">ROR1, NTRKR1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=0LI:3-(IMIDAZO[1,2-B]PYRIDAZIN-3-YLETHYNYL)-4-METHYL-N-{4-[(4-METHYLPIPERAZIN-1-YL)METHYL]-3-(TRIFLUOROMETHYL)PHENYL}BENZAMIDE'>0LI</scene></td></tr>
-<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=6tu9 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6tu9 OCA], [http://pdbe.org/6tu9 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6tu9 RCSB], [http://www.ebi.ac.uk/pdbsum/6tu9 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6tu9 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=6tu9 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6tu9 OCA], [https://pdbe.org/6tu9 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6tu9 RCSB], [https://www.ebi.ac.uk/pdbsum/6tu9 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6tu9 ProSAT]</span></td></tr>
 </table>
 == Disease ==
-[[http://www.uniprot.org/uniprot/ROR1_HUMAN ROR1_HUMAN]] The disease is caused by mutations affecting the gene represented in this entry.
+[https://www.uniprot.org/uniprot/ROR1_HUMAN ROR1_HUMAN] The disease is caused by mutations affecting the gene represented in this entry.
 == Function ==
-[[http://www.uniprot.org/uniprot/ROR1_HUMAN ROR1_HUMAN]] Has very low kinase activity in vitro and is unlikely to function as a tyrosine kinase in vivo (PubMed:25029443). Receptor for ligand WNT5A which activate downstream NFkB signaling pathway and may result in the inhibition of WNT3A-mediated signaling (PubMed:25029443, PubMed:27162350). In inner ear, crucial for spiral ganglion neurons to innervate auditory hair cells (PubMed:27162350).<ref>PMID:25029443</ref> <ref>PMID:27162350</ref>
+[https://www.uniprot.org/uniprot/ROR1_HUMAN ROR1_HUMAN] Has very low kinase activity in vitro and is unlikely to function as a tyrosine kinase in vivo (PubMed:25029443). Receptor for ligand WNT5A which activate downstream NFkB signaling pathway and may result in the inhibition of WNT3A-mediated signaling (PubMed:25029443, PubMed:27162350). In inner ear, crucial for spiral ganglion neurons to innervate auditory hair cells (PubMed:27162350).<ref>PMID:25029443</ref> <ref>PMID:27162350</ref>
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
@@ Line 25: / Line 25: @@
 __TOC__
 </StructureSection>
-[[Category: Human]]
+[[Category: Homo sapiens]]
 [[Category: Large Structures]]
-[[Category: Arrowsmith, C H]]
+[[Category: Arrowsmith CH]]
-[[Category: Bountra, C]]
+[[Category: Bountra C]]
-[[Category: Chatterjee, D]]
+[[Category: Chatterjee D]]
-[[Category: Edwards, A M]]
+[[Category: Edwards AM]]
-[[Category: Knapp, S]]
+[[Category: Knapp S]]
-[[Category: Mathea, S]]
+[[Category: Mathea S]]
-[[Category: Niininen, W]]
+[[Category: Niininen W]]
-[[Category: Preuss, F]]
+[[Category: Preuss F]]
-[[Category: Shin, D]]
+[[Category: Shin D]]
-[[Category: Ungureanu, D]]
+[[Category: Ungureanu D]]
-[[Category: Receptor transmembrane kinase pseudokinase small-molecule inhibitor]]
-[[Category: Signaling protein]]

6tu9

From Proteopedia

Current revision

The ROR1 Pseudokinase Domain Bound To Ponatinib

Structural highlights

Disease

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

Personal tools

Navigation

Search

Toolbox