Sandbox 121: Difference between revisions
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When B2AR is activated, the G-protein disassociates. A surrogate nanobody, <scene name='Sandbox_121/B2ar_struc/13'>Nb80</scene>, that is a camelid antibody produced to mimic the G-protein needed for an active state of the B2AR. | When B2AR is activated, the G-protein disassociates. A surrogate nanobody, <scene name='Sandbox_121/B2ar_struc/13'>Nb80</scene>, that is a camelid antibody produced to mimic the G-protein needed for an active state of the B2AR. | ||
Active B₂AR in complex with BI-167107: <scene name='Sandbox_121/B2ar_struc/7'>Polar</scene> and <scene name='Sandbox_121/B2ar_struc/8'>Hydrophobic</scene> Interactions | |||
{{clear}} | {{clear}} | ||
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---- | ---- | ||
[[Image:B2AR_Binding_Pocket_PolarInt_Act_In.JPG|right|thumb|alt= Alt text| The binding mode of isoproterenol and carazolol in B2AR. Hydrophobic residues are displayed in yellow. Polar interactions are displayed with residues in cyan, oxygen in red, and hydrogen in white. (a) A model of B2AR in its active state in complex with isoproterenol. | |||
(b) B2AR in its inactive state in complex with carazolol. |450px]] | |||
==='''Ligand Binding'''=== | |||
Ligands share several key interactions in the binding pocket including: | Ligands share several key interactions in the binding pocket including: | ||
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(ii) Hydrophobic interaction between ligand and Val117 in TM3, Phe193 | (ii) Hydrophobic interaction between ligand and Val117 in TM3, Phe193 | ||
in ECL2, Phe289 in TM6, and Phe290 inTM6. | in ECL2, Phe289 in TM6, and Phe290 inTM6. | ||
==='''Conformational Change'''=== | |||
When an agonist is in the binding pocket a 2.1Å inward movement of TM5 at Ser207 is observed. This bulge at ser207 allows for a hydrogen bond between the ligand and the receptor. This interaction appears to be a key event in activation. | |||
<Structure load='Morph_2rh1_on_3p0g_all_atoms.pdb' size='500' frame='true' align='right' caption='Conformational Changes in B2AR from Inactive State(2rh1) to Active State(3p0g)' scene='Sandbox_254/B2ar_morph_ser_glu_arg/32'/> | |||
[[Image:B2AR-Binding_Pocket_OH.JPG|thumb|left|alt= Alt text| Models of isoproternol binding to two B2AR structures. (a) Inactive B2AR: 4.78Å distance between the catechol-OH of the ligand and Ser207 of TM5 is too large for a H-bond. (b) Active B2AR: A hydrogen bond distance of 2.17Å between the catechol-OH of the ligand and Ser207 on TM5 is shown. |450px]] | |||
[[Image:B2AR-Binding_Pocket_clash.JPG|thumb|left|alt= Alt text| Model of carazolol binding to B2AR structure. (a) Active B2AR: there is a steric clash between the ligand and Ser207 of TM5. (b)Inactive B2AR: carazolol in B2AR fits perfectly and blocks the agonist from entering the binding pocket. |450px]] | |||
{{clear}} | |||
After the agonist binds, there is a rearrangement of interactions between residues located beneath the binding pocket that contributes to a rotation and outward movement of TM6 at Phe282. This change is associated with the breaking of the ionic lock between Glu268 in TM6 and Arg131 in TM3, resulting in an 11.4Å outward movement of the helix at the cytoplasmic face. | After the agonist binds, there is a rearrangement of interactions between residues located beneath the binding pocket that contributes to a rotation and outward movement of TM6 at Phe282. This change is associated with the breaking of the ionic lock between Glu268 in TM6 and Arg131 in TM3, resulting in an 11.4Å outward movement of the helix at the cytoplasmic face. | ||
When an agonist is in the <scene name='Sandbox_254/B2ar_morph_ser_glu_arg/23'>binding pocket</scene> a 2.1Å inward movement of TM5 at Ser207 is observed. This bulge at ser207 allows for a hydrogen bond between the ligand and the receptor. This interaction appears to be a key event in activation. | |||
After the agonist binds, there is a rearrangement of interactions between residues located beneath the binding pocket that contributes to a rotation and outward movement of TM6 at Phe282. This change is associated with the breaking of the ionic lock between Glu268 in TM6 and Arg131 in TM3, resulting in an 11.4Å outward movement of the helix at the cytoplasmic face. | |||
==='''Molecular Morph'''=== | ==='''Molecular Morph'''=== | ||
The coordinates for molecular morphs between inactive state of B2AR (2rh1) and active state (3p0g) were generated using iPyMOL and eMovie (http://www.weizmann.ac.il/ISPC/eMovie.html). Morphs, a series of 10 linear interpolations between a starting and finishing model, are useful when viewing the transition of a conformational change. This model of B2AR using morphs should not be thought of as precise animation of conformational changes upon activation but rather as a comparison of the inactive state to the active state. | The coordinates for molecular morphs between inactive state of B2AR (2rh1) and active state (3p0g) were generated using iPyMOL and eMovie (http://www.weizmann.ac.il/ISPC/eMovie.html). Morphs, a series of 10 linear interpolations between a starting and finishing model, are useful when viewing the transition of a conformational change. This model of B2AR using morphs should not be thought of as precise animation of conformational changes upon activation but rather as a comparison of the inactive state to the active state. | ||
