SandboxPKA: Difference between revisions
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The fusion of the gene encoding c-Abl with the breakpoint cluster region (BCR) gene, results in the formation of a fusion protein, BCR-Abl, in which all of c-Abl is preserved without mutation, except for the “cap” region upstream of the SH3 domain. | The fusion of the gene encoding c-Abl with the breakpoint cluster region (BCR) gene, results in the formation of a fusion protein, BCR-Abl, in which all of c-Abl is preserved without mutation, except for the “cap” region upstream of the SH3 domain. | ||
===[['''Kinase domain''']]=== | |||
=='''Kinase domain'''== | |||
Protein kinases are characterized by an architecture that enables distal parts of the enzyme to be linked by conserved hydrophobic elements. Kynase domain is composed by N-lobe and a C-lobe, and the adenine ring of ATP is buried at the base of the cleft between the two lobes. | Protein kinases are characterized by an architecture that enables distal parts of the enzyme to be linked by conserved hydrophobic elements. Kynase domain is composed by N-lobe and a C-lobe, and the adenine ring of ATP is buried at the base of the cleft between the two lobes. | ||
==='''N-lobe'''=== | ===='''N-lobe'''==== | ||
Each kinase consists of two structurally and functionally distinct lobes that contribute to both catalysis and regulation. | Each kinase consists of two structurally and functionally distinct lobes that contribute to both catalysis and regulation. | ||
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• '''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>[Johnson, D.A. et al. (2001) Dynamics of cAMP-dependent protein kinase. Chem. Rev. 101, 2243–2270].</Ref> The C-helix contains another conserved residue, Glu or Asp, that bridges to Lys located in P-loop. This bridge is really important for catalysis process. | • '''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>[Johnson, D.A. et al. (2001) Dynamics of cAMP-dependent protein kinase. Chem. Rev. 101, 2243–2270].</Ref> The C-helix contains another conserved residue, Glu or Asp, that bridges to Lys located in P-loop. This bridge is really important for catalysis process. | ||
=== '''<scene name='SandboxPKA/Catalytic_domain/2'>Catalytic domain</scene>''' == | |||
It is responsible of both, ATP binding as well as protein binding. | |||
The crystal structure of the catalytic domain of Abl was reported by Schindler et. al in 2000. The binding of STI-571 promotes the adoption by the kinase of an inactive conformation in which a centrally located "activation loop" is not phosphorylated. | |||
<scene name='SandboxPKA/Ac/1'>TextToBeDisplayed</scene> | |||
Catalitic subunit of c-Abl protein is composed by two different regions: | |||
• '''ATP-binding pocket''': is mainly mediated by alfa-helix | |||
• '''Protein-binding pocket''': lamina-B domain | |||
< | <StructureSection load='1OPK' size='300' side='right' caption='c-Abl tyrosine kinase' scene='SandboxPKA/Abl1/4'> | ||
=== ''' | |||
</StructureSection> | |||
== '''Bcr-Abl tyrosine kinase''' == | == '''Bcr-Abl tyrosine kinase''' == | ||
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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. 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> | ||
== '''Reaction''' == | |||
Protein kinases are a group of enzymes that possess a catalytic subunit that transfers the gamma (terminal) phosphate from nucleotide triphosphates (often ATP) to one or more amino acid residues in a protein substrate side chain, resulting in a conformational change affecting side protein function. | |||
The enzymes are classified into two broad groups, characterised with respect to substrate specificity: | |||
- '''Serine/threonine kinases''' | |||
- '''Tyrosine specific kinases''': c-Abl is included in this group | |||
<ref>Leukemia research 34 (10): 1255–1268. doi:10.1016/j.leukres.2010.04.016. PMID 2053738</ref> | |||
[[Image:Almu_reaction.jpg]] | |||