SandboxPKA: Difference between revisions

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Proteopedia Page Contributors and Editors (what is this?)Proteopedia Page Contributors and Editors (what is this?)

Cristina Murga, Joel L. Sussman

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 •	'''Gly-rich loop (GxGxxG):'''  this loop folds over the nucleotide and positions the γ-phosphate of ATP for catalysis and is the most ﬂexible part of the N-lobe.
 •	'''<scene name='Dasatinib/Mpl/4'>P-Loop Movement</scene>'''<  often referred to as the Walker-A motif (GxxxxGKT/S) <Ref>PMID: 12468712</Ref>. In this loop there is a higly conserved residue (usually Lys) which is able to form a salt bridge with the C-helix.
 •	'''C-helix''':  is a unique helix present in the N-lobe. It is very dynamic and plays a key role as a regulatory element in the protein kinase molecule. C-helix occupies a strategically important position between the two lobes. The C-helix connects many different parts of the molecule and serves as a ‘‘signal integration motif’’ <Ref>PMID: 11749372</Ref> The C-helix contains another conserved residue, Glu or Asp, that bridges to a Lys residue located in the P-loop. This bridge is essential for the catalytic process.
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 - The '''catalytic loop''' is composed by β6 and β7, whereas β8 and β9 strands flank the DGF motif, where the aspartic/glutamic residue is critical for recognizing one of the ATP-bound Mg++ ions
-- The '''<scene name='Dasatinib/Mact/1'>Activation Loop Movement</scene>''' contains Tyr412 responsible for activation of the kinase activity.
+- The '''<scene name='Dasatinib/Mact/1'>Activation Loop Movement</scene>''' involves Tyr412 responsible for activation of the kinase activity.
-- The unactivated, autoinhibited conformation [in which the Asp-810-Phe-811-Gly-812 (DFG) triad at the beginning of the A-loop is in the “DFG-out” conformation, can <scene name='Dasatinib/Mdfg/3'>move</scene> when ATP Tyr412 is phosphorlated, rising an active conformation. <Ref>PMID: 19164557</Ref>
+- In the unactivated, autoinhibited conformation, the Asp-810-Phe-811-Gly-812 (DFG) triad at the beginning of the A-loop is in the “DFG-out” conformation. The DFG motif can <scene name='Dasatinib/Mdfg/3'>move</scene> when Tyr412 is phosphorylated, thus promoting the change towards the active conformation. <Ref>PMID: 19164557</Ref>
 - The '''myristoyl group''' complements activation loop in turning on and off c-Abl protein. It has been shown to be a key regulator of this kinase.
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 [[Image:Almu_reaction.jpg|thumb|right]]
-The kinases are classified into several broad groups depending on their substrate specificity (serine/threonine; sistidine; ...). c-Abl is included in the group of '''Tyrosine specific kinases''':
+The kinases are classified into several broad groups depending on their substrate specificity. c-Abl is included in the group of '''Tyrosine kinases''':
 <ref>Leukemia research 34 (10): 1255–1268. doi:10.1016/j.leukres.2010.04.016. PMID 2053738</ref>
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 ==== Bosutinib  (SKI-606)====
-On September 4, 2012, the U. S. Food and Drug Administration approved bosutinib tablets (Bosulif, Pfizer, Inc.) for the treatment of chronic, accelerated, or blast phase Philadelphia chromosome positive (Ph+) chronic myelogenous leukemia (CML) in adult patients with resistance or intolerance to prior therapy. <ref>http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm318203.htm</ref>
+Bosutinib has been seen to be active in chronic myeloid leukemia after imatinib and dasatinib and/or nilotinib therapy failure. <ref>PMID: 22371878</ref> On September 4, 2012, the U. S. Food and Drug Administration approved bosutinib tablets (Bosulif, Pfizer, Inc.) for the treatment of chronic, accelerated, or blast phase Philadelphia chromosome positive (Ph+) CML in adult patients with resistance or intolerance to prior therapy. <ref>http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm318203.htm</ref>
 <scene name='SandboxPKA/Bosutinib/2'>Bosutinib's structure</scene> is based on a quinoline scaffold and is structurally related to the AstraZeneca quinazoline template. <ref>PMID: 16172030</ref>
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 [[Image:PONATINIB.jpg|thumb|left|Ponatinib bound to Abl]]
-Ponatinib was identified using structure base drug design and focused synthetic libraries of trisubstituted purine analogs. The substance potently inhibits, on nanomolar scale, Src and Bcr-Abl kinases including many common imatinib resistant Bcr-Abl mutations, like T315I mutation. The key structural feature of the molecule is a carbon-carbon triple bond linkage that makes productive hydrophobic contact with the side chain of I315, allowing inhibition of the T315I mutant. The triple bond also acts as an inflexible connector that enforces correct positioning of the two binding segments of AP24534 into their established binding pockets. AP24534 maintains an extensive hydrogen-bonding network and occupies a region of the kinase that overlaps significantly with the imatinib binding site.  <ref>PMID:19878872</ref>
+Ponatinib was identified using structure base drug design and focused synthetic libraries of trisubstituted purine analogs. It can inhibit, on nanomolar scale, Src and Bcr-Abl kinases including many common imatinib resistant Bcr-Abl mutations, like T315I mutation. The key structural feature of the molecule is a carbon-carbon triple bond linkage that makes productive hydrophobic contact with the side chain of I315, allowing inhibition of the T315I mutant. The triple bond also acts as an inflexible connector that enforces correct positioning of the two binding segments of AP24534 into their established binding pockets. AP24534 maintains an extensive hydrogen-bonding network and occupies a region of the kinase that overlaps significantly with the imatinib binding site.  <ref>PMID:19878872</ref>
+<scene name='SandboxPKA/Ponatinib_bound_to_abl/1'>Ponatinib bound to c-Abl kinase domain</scene>
+<scene name='52/521153/Ponatinib_bound_to_abl/2'>Ponatinib bound to c-Abl kinase domain</scene>
 == '''Resistance''' ==