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4otw

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Revision as of 06:52, 13 August 2014

HER3 pseudokinase domain bound to bosutinib

Structural highlights

4otw is a 1 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:
Gene:	ERBB3, HER3 (HUMAN)
Activity:	Receptor protein-tyrosine kinase, with EC number 2.7.10.1
Resources:	FirstGlance, OCA, RCSB, PDBsum

Disease

[ERBB3_HUMAN] Defects in ERBB3 are the cause of lethal congenital contracture syndrome type 2 (LCCS2) [MIM:607598]; also called Israeli Bedouin multiple contracture syndrome type A. LCCS2 is an autosomal recessive neurogenic form of a neonatally lethal arthrogryposis that is associated with atrophy of the anterior horn of the spinal cord. The LCCS2 syndrome is characterized by multiple joint contractures, anterior horn atrophy in the spinal cord, and a unique feature of a markedly distended urinary bladder. The phenotype suggests a spinal cord neuropathic etiology.^[1]

Function

[ERBB3_HUMAN] Binds and is activated by neuregulins and NTAK.^[2]

Publication Abstract from PubMed

Human epidermal growth factor receptor 3 (HER3) is a receptor tyrosine kinase that lacks catalytic activity but is essential for cellular homeostasis due to its ability to allosterically activate EGFR and HER2. Although catalytically inactive, HER3 binds ATP tightly, hinting at a possible role of the nucleotide-binding pocket in modulating HER3 function. We report a structure of the HER3 pseudokinase bound to the ATP-competitive inhibitor bosutinib. Previously solved structures show that bosutinib can potently interact with multiple kinase domain conformations. In complex with HER3, bosutinib binds to yet another conformation, which is nearly identical to that observed in the HER3-ATP complex. Interestingly, occupation of the ATP-binding site by bosutinib improves the ability of HER3 to act as an allosteric activator of EGFR in vitro by increasing the affinity of the HER3-EGFR heterodimer in a membrane-dependent manner.

An ATP-Competitive Inhibitor Modulates the Allosteric Function of the HER3 Pseudokinase.,Littlefield P, Moasser MM, Jura N Chem Biol. 2014 Mar 18. pii: S1074-5521(14)00069-6. doi:, 10.1016/j.chembiol.2014.02.011. PMID:24656791^[3]

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

References

↑ Narkis G, Ofir R, Manor E, Landau D, Elbedour K, Birk OS. Lethal congenital contractural syndrome type 2 (LCCS2) is caused by a mutation in ERBB3 (Her3), a modulator of the phosphatidylinositol-3-kinase/Akt pathway. Am J Hum Genet. 2007 Sep;81(3):589-95. Epub 2007 Jul 24. PMID:17701904 doi:S0002-9297(07)61355-X
↑ Kinugasa Y, Ishiguro H, Tokita Y, Oohira A, Ohmoto H, Higashiyama S. Neuroglycan C, a novel member of the neuregulin family. Biochem Biophys Res Commun. 2004 Sep 3;321(4):1045-9. PMID:15358134 doi:10.1016/j.bbrc.2004.07.066
↑ Littlefield P, Moasser MM, Jura N. An ATP-Competitive Inhibitor Modulates the Allosteric Function of the HER3 Pseudokinase. Chem Biol. 2014 Mar 18. pii: S1074-5521(14)00069-6. doi:, 10.1016/j.chembiol.2014.02.011. PMID:24656791 doi:http://dx.doi.org/10.1016/j.chembiol.2014.02.011

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/4otw"

@@ Line 2: / Line 2: @@
 <StructureSection load='4otw' size='340' side='right' caption='[[4otw]], [[Resolution|resolution]] 2.51&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[4otw]] 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=4OTW OCA]. <br>
+<table><tr><td colspan='2'>[[4otw]] 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=4OTW OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4OTW FirstGlance]. <br>
 </td></tr><tr><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=DB8:4-[(2,4-DICHLORO-5-METHOXYPHENYL)AMINO]-6-METHOXY-7-[3-(4-METHYLPIPERAZIN-1-YL)PROPOXY]QUINOLINE-3-CARBONITRILE'>DB8</scene><br>
 <tr><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">ERBB3, HER3 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
-<tr><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Glucokinase Glucokinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.1.2 2.7.1.2] </span></td></tr>
+<tr><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Receptor_protein-tyrosine_kinase Receptor protein-tyrosine kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.10.1 2.7.10.1] </span></td></tr>
 <tr><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4otw FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4otw OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4otw RCSB], [http://www.ebi.ac.uk/pdbsum/4otw PDBsum]</span></td></tr>
 <table>
@@ Line 18: / Line 18: @@
 An ATP-Competitive Inhibitor Modulates the Allosteric Function of the HER3 Pseudokinase.,Littlefield P, Moasser MM, Jura N Chem Biol. 2014 Mar 18. pii: S1074-5521(14)00069-6. doi:, 10.1016/j.chembiol.2014.02.011. PMID:24656791<ref>PMID:24656791</ref>
-From MEDLINEÂ®/PubMedÂ®, a database of the U.S. National Library of Medicine.<br>
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
 </div>
 == References ==

4otw

From Proteopedia

Revision as of 06:52, 13 August 2014

HER3 pseudokinase domain bound to bosutinib

Structural highlights

Disease

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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