User:Randy Bennett/Sandbox 1: Difference between revisions

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==BCR-Abl and Gleevec)==


Chronic Myelogenous Leukemia (CML) results from a gene defect in a haematological stem cell, <scene name='Imatinib/Bcr-bl/1'>producing the kinase, BCR-Abl. Compared to the tightly regulated c-Abl kinase, BCR-Abl has a truncated auto-regulatory domain, leading to constitutive activation of its tyrosine kinase activity. The result of this nearly limitless activation is unregulated phosphorylation of downstream receptors leading to uncontrolled growth and survival of leukemic cells. Like many other receptor tyrosine kinases, BCR-Abl is at an equilibrium between two states, an active state and an auto-regulated inactive state. Imatinib functions by binding in the ATP binding site and stabilizing the inactive conformation of BCR-Abl, in which the well known "DFG triad" is in the "out" conformation. A critically important residue, Thr 315, is known as the gatekeeper residue. In the inactive DFG out conformation, Thr 315 shifts to allow binding of Imatinib and the activation loop loops back over the top of the protein . It is this Thr 315 that is believed to give Imatinib its remarkable binding specificity. Although the DFG-out conformation has been seen in other kinases like B-Raf, p38, KDR, Flt-3, and insulin receptor kinase, Imatinib does not bind any of these kinases. The primary reason is appears to be that all of these kinases have a residue at position 315 that is larger than the threonine present in BCR-Abl. These larger residues block the pocket formed by the DFG out conformation in which Imatinib binds, preventing Imatinib from stabilizing these compounds.[2] Interestingly, both KIT and PDGFR have nearly identical DFG out conformations and have the same Thr residue at this gatekeeper position, explaining how Imatinib binds and inhibits these proteins commonly involved in Gastrointestinal Stromal Tumors. Imatinib resistant forms of BCR-Abl often have mutations at this gatekeeper position, the most prominent being T315I.[3] In BCR-Abl, Imatinib is bound by with H-bonds to residues Met 318, Thr 315, Glu 286, Asp 381, Ile 380 & His 361 along with hydrophobic interactions with residues Ile 360, Ala 380, Met 290, Val 299, Lys 271, Ala 269, Val 256, & Phe 317 firmly securing the inhibitor in place and stabilizing the inhibited conformation of the kinase.[4]
To see morphs of the movement of key structural elements Click: DFG Movement, P-Loop Movement, & the Activation Loop Movement.
</StructureSection>==Your Heading Here (maybe something like 'Structure')==
<StructureSection load='1stp' size='340' side='right' caption='Caption for this structure' scene=''>
This is a default text for your page '''Randy Bennett/Sandbox 1'''. Click above on '''edit this page''' to modify. Be careful with the &lt; and &gt; signs.
You may include any references to papers as in: the use of JSmol in Proteopedia <ref>DOI 10.1002/ijch.201300024</ref> or to the article describing Jmol <ref>PMID:21638687</ref> to the rescue.
== Function ==
== Disease ==
== Relevance ==
== Structural highlights ==
This is a sample scene created with SAT to <scene name="/12/3456/Sample/1">color</scene> by Group, and another to make <scene name="/12/3456/Sample/2">a transparent representation</scene> of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.
</StructureSection>
== References ==
<references/>

Revision as of 22:36, 20 October 2015

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