Sandbox Reserved 1713: Difference between revisions

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<StructureSection load='1stp' size='340' side='right' caption='Caption for this structure' scene=''>
<StructureSection load='1stp' size='340' side='right' caption='Caption for this structure' scene=''>
== Structure & Function ==
== Structure & Function ==
The active state of the kinase is when two monomers have completed a conformational change and moved across the membrane to form a <scene name='90/904317/Dimer_full_colored/3'>dimer</scene>.
===Domains===
===Domains===
[[Image:2d_image.jpg|400 px|center|thumb|Fig.1 Anaplastic Lymphoma Kinase and its domains. The region from NTR to the MAM is the Heparin Binding Domain. The TNFL-PXL are the extracellular domains and the EGF is the domain that binds the extracellular region with the extracellular region of the transmembrane. The TMH is the transmembrane domain. The kinase domain is the intracellular portion of the ALK.]]
[[Image:2d_image.jpg|400 px|center|thumb|Fig.1 Anaplastic Lymphoma Kinase and its domains. The region from NTR to the MAM is the Heparin Binding Domain. The TNFL-PXL are the extracellular domains and the EGF is the domain that binds the extracellular region with the extracellular region of the transmembrane. The TMH is the transmembrane domain. The kinase domain is the intracellular portion of the ALK.]]
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===Conformational Change===
===Conformational Change===
The anaplastic lymphoma kinase activating ligand (ALKAL) binds to the <scene name='90/904318/Alk-alkal_binding_surface/2'>binding surface</scene> on the ALK at the TNFL domain. This induces a conformational change which allows for the PXL and the GlyR domains to hinge forward.<ref>DOI: 10.1038/s41586-021-04140-8</ref> (Figure 2) ALK's TNFL has <scene name='90/904318/Binding_surface_with_residues/3'>residues</scene> E978, E974, E859, and Y966 that form salt bridges with R123, R133, R136, R140, and R117 on ALKAL that allow for activation, leading to <scene name='90/904317/Dimer_full_colored/3'>dimerization</scene> of two ALK-ALKAL monomers.
The anaplastic lymphoma kinase activating ligand (ALKAL) binds to the <scene name='90/904318/Alk-alkal_binding_surface/2'>binding surface</scene> on the ALK at the TNFL domain. This induces a conformational change which allows for the PXL and the GlyR domains to hinge forward.<ref>DOI: 10.1038/s41586-021-04140-8</ref> (Figure 2) ALK's TNFL has <scene name='90/904318/Binding_surface_with_residues/3'>residues</scene> E978, E974, E859, and Y966 that form salt bridges with R123, R133, R136, R140, and R117 on ALKAL that allow for activation, leading to <scene name='90/904317/Dimer_full_colored/3'>dimerization</scene> of two ALK-ALKAL monomers.
===Movement across the membrane===
===Membrane Guidance of ALKAL to ALK===
The negatively charged phosphate groups on the cell membrane interact with the highly conserved positively charged residues on ALKAL ligand that face the membrane, which stabilizes the ligand to bind to ALK even better. <ref>DOI: 10.1038/s41586-021-04140-8</ref>
The negatively charged phosphate groups on the cell membrane interact with a highly conserved positively charged <scene name='90/904318/Alkalbindingsurfacewmembrane/1'>helix</scene> on ALKAL that faces the membrane. These <scene name='90/904318/Alkal1membraneinteraction/2'>residues that interact with the cell membrane</scene> guides ALKAL to ALK and correctly positions ALKAL for its binding surface to face ALK's binding surface, which allows for a more favorable interaction. <ref>DOI: 10.1038/s41586-021-04140-8</ref>
== Disease ==
== Disease ==
There are many mutations that could take place causing constitutive receptor activation, enhancement between the interaction of receptors or stabilization of active receptors are known to relate to oncogenic potentials.
There are many mutations that could take place causing constitutive receptor activation, enhancement between the interaction of receptors or stabilization of active receptors are known to relate to oncogenic potentials.
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