3ms9: Difference between revisions

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{{STRUCTURE_3ms9|  PDB=3ms9  |  SCENE=  }}
==ABL kinase in complex with imatinib and a fragment (FRAG1) in the myristate pocket==
===ABL kinase in complex with imatinib and a fragment (FRAG1) in the myristate pocket===
<StructureSection load='3ms9' size='340' side='right' caption='[[3ms9]], [[Resolution|resolution]] 1.80&Aring;' scene=''>
{{ABSTRACT_PUBMED_20450175}}
== Structural highlights ==
<table><tr><td colspan='2'>[[3ms9]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Mus_musculus Mus musculus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3MS9 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3MS9 FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=MS9:METHYL+2-AMINO-4-CHLOROBENZOATE'>MS9</scene>, <scene name='pdbligand=STI:4-(4-METHYL-PIPERAZIN-1-YLMETHYL)-N-[4-METHYL-3-(4-PYRIDIN-3-YL-PYRIMIDIN-2-YLAMINO)-PHENYL]-BENZAMIDE'>STI</scene></td></tr>
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3mss|3mss]]</td></tr>
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">Abl1, Abl ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=10090 Mus musculus])</td></tr>
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Non-specific_protein-tyrosine_kinase Non-specific protein-tyrosine kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.10.2 2.7.10.2] </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=3ms9 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3ms9 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3ms9 RCSB], [http://www.ebi.ac.uk/pdbsum/3ms9 PDBsum]</span></td></tr>
</table>
== Evolutionary Conservation ==
[[Image:Consurf_key_small.gif|200px|right]]
Check<jmol>
  <jmolCheckbox>
    <scriptWhenChecked>select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/ms/3ms9_consurf.spt"</scriptWhenChecked>
    <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
    <text>to colour the structure by Evolutionary Conservation</text>
  </jmolCheckbox>
</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/chain_selection.php?pdb_ID=2ata ConSurf].
<div style="clear:both"></div>
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Allosteric inhibitors of Bcr-Abl have emerged as a novel therapeutic option for the treatment of CML. Using fragment-based screening, a search for novel Abl inhibitors that bind to the myristate pocket was carried out. Here we show that not all myristate ligands are functional inhibitors, but that the conformational state of C-terminal helix_I is a structural determinant for functional activity. We present an NMR-based conformational assay to monitor the conformation of this crucial helix_I and show that myristate ligands that bend helix_I are functional antagonists, whereas ligands that bind to the myristate pocket but do not induce this conformational change are kinase agonists. Activation of c-Abl by allosteric agonists has been confirmed in a biochemical assay.


==Function==
Binding or bending: distinction of allosteric Abl kinase agonists from antagonists by an NMR-based conformational assay.,Jahnke W, Grotzfeld RM, Pelle X, Strauss A, Fendrich G, Cowan-Jacob SW, Cotesta S, Fabbro D, Furet P, Mestan J, Marzinzik AL J Am Chem Soc. 2010 May 26;132(20):7043-8. PMID:20450175<ref>PMID:20450175</ref>
[[http://www.uniprot.org/uniprot/ABL1_MOUSE ABL1_MOUSE]] Non-receptor tyrosine-protein kinase that plays a role in many key processes linked to cell growth and survival such as cytoskeleton remodeling in response to extracellular stimuli, cell motility and adhesion, receptor endocytosis, autophagy, DNA damage response and apoptosis. Coordinates actin remodeling through tyrosine phosphorylation of proteins controlling cytoskeleton dynamics like WASF3 (involved in branch formation); ANXA1 (involved in membrane anchoring); DBN1, DBNL, CTTN, RAPH1 and ENAH (involved in signaling); or MAPT and PXN (microtubule-binding proteins). Phosphorylation of WASF3 is critical for the stimulation of lamellipodia formation and cell migration. Involved in the regulation of cell adhesion and motility through phosphorylation of key regulators of these processes such as BCAR1, CRK, CRKL, DOK1, EFS or NEDD9. Phosphorylates multiple receptor tyrosine kinases and more particularly promotes endocytosis of EGFR, facilitates the formation of neuromuscular synapses through MUSK, inhibits PDGFRB-mediated chemotaxis and modulates the endocytosis of activated B-cell receptor complexes. Other substrates which are involved in endocytosis regulation are the caveolin (CAV1) and RIN1. Moreover, ABL1 regulates the CBL family of ubiquitin ligases that drive receptor down-regulation and actin remodeling. Phosphorylation of CBL leads to increased EGFR stability. Involved in late-stage autophagy by regulating positively the trafficking and function of lysosomal components. ABL1 targets to mitochondria in response to oxidative stress and thereby mediates mitochondrial dysfunction and cell death. ABL1 is also translocated in the nucleus where it has DNA-binding activity and is involved in DNA-damage response and apoptosis. Many substrates are known mediators of DNA repair: DDB1, DDB2, ERCC3, ERCC6, RAD9A, RAD51, RAD52 or WRN. Activates the proapoptotic pathway when the DNA damage is too severe to be repaired. Phosphorylates TP73, a primary regulator for this type of damage-induced apoptosis. Phosphorylates the caspase CASP9 on 'Tyr-191' and regulates its processing in the apoptotic response to DNA damage. Phosphorylates PSMA7 that leads to an inhibition of proteasomal activity and cell cycle transition blocks.<ref>PMID:8194526</ref> <ref>PMID:7780740</ref> <ref>PMID:9109492</ref> <ref>PMID:11279004</ref> <ref>PMID:11350980</ref> <ref>PMID:11279131</ref> <ref>PMID:12107171</ref> <ref>PMID:12748290</ref> <ref>PMID:14993293</ref> <ref>PMID:19903482</ref> <ref>PMID:19878872</ref>


==About this Structure==
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
[[3ms9]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Mus_musculus Mus musculus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3MS9 OCA].
</div>


==Reference==
==See Also==
<ref group="xtra">PMID:020450175</ref><references group="xtra"/><references/>
*[[Tyrosine kinase|Tyrosine kinase]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Mus musculus]]
[[Category: Mus musculus]]
[[Category: Non-specific protein-tyrosine kinase]]
[[Category: Non-specific protein-tyrosine kinase]]
[[Category: Cowan-Jacob, S W.]]
[[Category: Cowan-Jacob, S W]]
[[Category: Fendrich, G.]]
[[Category: Fendrich, G]]
[[Category: Rummel, G.]]
[[Category: Rummel, G]]
[[Category: Fb]]
[[Category: Fb]]
[[Category: Fragment-based screening]]
[[Category: Fragment-based screening]]

Revision as of 20:13, 18 December 2014

ABL kinase in complex with imatinib and a fragment (FRAG1) in the myristate pocketABL kinase in complex with imatinib and a fragment (FRAG1) in the myristate pocket

Structural highlights

3ms9 is a 2 chain structure with sequence from Mus musculus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:, ,
Gene:Abl1, Abl (Mus musculus)
Activity:Non-specific protein-tyrosine kinase, with EC number 2.7.10.2
Resources:FirstGlance, OCA, RCSB, PDBsum

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

Allosteric inhibitors of Bcr-Abl have emerged as a novel therapeutic option for the treatment of CML. Using fragment-based screening, a search for novel Abl inhibitors that bind to the myristate pocket was carried out. Here we show that not all myristate ligands are functional inhibitors, but that the conformational state of C-terminal helix_I is a structural determinant for functional activity. We present an NMR-based conformational assay to monitor the conformation of this crucial helix_I and show that myristate ligands that bend helix_I are functional antagonists, whereas ligands that bind to the myristate pocket but do not induce this conformational change are kinase agonists. Activation of c-Abl by allosteric agonists has been confirmed in a biochemical assay.

Binding or bending: distinction of allosteric Abl kinase agonists from antagonists by an NMR-based conformational assay.,Jahnke W, Grotzfeld RM, Pelle X, Strauss A, Fendrich G, Cowan-Jacob SW, Cotesta S, Fabbro D, Furet P, Mestan J, Marzinzik AL J Am Chem Soc. 2010 May 26;132(20):7043-8. PMID:20450175[1]

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

See Also

References

  1. ↑ Jahnke W, Grotzfeld RM, Pelle X, Strauss A, Fendrich G, Cowan-Jacob SW, Cotesta S, Fabbro D, Furet P, Mestan J, Marzinzik AL. Binding or bending: distinction of allosteric Abl kinase agonists from antagonists by an NMR-based conformational assay. J Am Chem Soc. 2010 May 26;132(20):7043-8. PMID:20450175 doi:10.1021/ja101837n

3ms9, resolution 1.80Å

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OCA
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