The Structure of PI3K: Difference between revisions
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==The Catalytic Subunit== | ==The Catalytic Subunit== | ||
<StructureSection load='1dq8' size='500' side='right' scene='User:David_Canner/Sandbox_P/Full/4' caption='Structure of PI3K p110, ([[3hhm]])'> | |||
===The Catalytic Subunit (P110) of Class 1 PI3Ks=== | ===The Catalytic Subunit (P110) of Class 1 PI3Ks=== | ||
The catalytic subunit, P110 has several isoforms that associate with different classes of PI3Ks. P110α, β, and δ associate with Class IA PI3Ks while p110γ associates with Class 1B PI3ks. <ref name="Wymann"/> The <scene name='User:David_Canner/Sandbox_P/Full/1'>p110α subunit contains several domains including</scene> an N-terminal adaptor-binding domain (ABD), a Ras binding domain (RBD) a C2 domain that likely binds to the cellular membrane, a helical domain (HD) with unknown function, and the actual catalytic kinase domain. <ref name="Amzel"> PMID: 19805105 </ref> The actions of these domains are coordinated by the nSH2 communicating domain in p85. | The catalytic subunit, P110 has several isoforms that associate with different classes of PI3Ks. P110α, β, and δ associate with Class IA PI3Ks while p110γ associates with Class 1B PI3ks. <ref name="Wymann"/> The <scene name='User:David_Canner/Sandbox_P/Full/1'>p110α subunit contains several domains including</scene> an N-terminal adaptor-binding domain (ABD), a Ras binding domain (RBD) a C2 domain that likely binds to the cellular membrane, a helical domain (HD) with unknown function, and the actual catalytic kinase domain. <ref name="Amzel"> PMID: 19805105 </ref> The actions of these domains are coordinated by the nSH2 communicating domain in p85. | ||
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Although no <scene name='User:David_Canner/Sandbox_P/Inhibitor_main/4'>crystal structure of PI3K</scene> with bound substate analog has been solved, a model for PIP2 phosphorylation has been developed and is generally supported. <ref name="Walker2">PMID:10580505</ref> In this model, the headgroup of PIP2 is <scene name='User:David_Canner/Sandbox_P/Catalytic_cavity/2'>positioned in a cavity</scene> between the <scene name='User:David_Canner/Sandbox_P/Catalytic_site/1'>C-terminal helix 12 of the kinase domain, the “activation” loop, and the “catalytic” loop</scene>. This puts the 5-phosphate of PIP2 near Lys 973 and the <scene name='User:David_Canner/Sandbox_P/Catalytic_site_atp_lys/1'>I-phosphate of ATP near Lys 807 and Lys 808</scene>. The <scene name='User:David_Canner/Sandbox_P/Catalytic_site_pip2/1'>basic residues Arg 947</scene> and Lys 973 can bind the 4-Phosphate of PIP2 and help provide the Class I PI3Ks with their specificity for PIP2. Once PIP2 and ATP are bound, it is believed <scene name='User:David_Canner/Sandbox_P/Catalytic_site_his/1'>His 948 rotates to interact with PIP2</scene>, deprotonating it at the C-3 Hydroxyl position creating a nucleophile. This nucleophile subsequently attacks the gamma phosphate of ATP producing PIP3. <ref name="Walker2"/> | Although no <scene name='User:David_Canner/Sandbox_P/Inhibitor_main/4'>crystal structure of PI3K</scene> with bound substate analog has been solved, a model for PIP2 phosphorylation has been developed and is generally supported. <ref name="Walker2">PMID:10580505</ref> In this model, the headgroup of PIP2 is <scene name='User:David_Canner/Sandbox_P/Catalytic_cavity/2'>positioned in a cavity</scene> between the <scene name='User:David_Canner/Sandbox_P/Catalytic_site/1'>C-terminal helix 12 of the kinase domain, the “activation” loop, and the “catalytic” loop</scene>. This puts the 5-phosphate of PIP2 near Lys 973 and the <scene name='User:David_Canner/Sandbox_P/Catalytic_site_atp_lys/1'>I-phosphate of ATP near Lys 807 and Lys 808</scene>. The <scene name='User:David_Canner/Sandbox_P/Catalytic_site_pip2/1'>basic residues Arg 947</scene> and Lys 973 can bind the 4-Phosphate of PIP2 and help provide the Class I PI3Ks with their specificity for PIP2. Once PIP2 and ATP are bound, it is believed <scene name='User:David_Canner/Sandbox_P/Catalytic_site_his/1'>His 948 rotates to interact with PIP2</scene>, deprotonating it at the C-3 Hydroxyl position creating a nucleophile. This nucleophile subsequently attacks the gamma phosphate of ATP producing PIP3. <ref name="Walker2"/> | ||
</StructureSection> | </StructureSection> | ||
==Additional Resources== | ==Additional Resources== | ||
