Sandbox 121: Difference between revisions

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==='''Background Information'''===
==='''Background Information'''===
[[Image:B2AR-Adernergic synapse.JPG|thumb|alt= Alt text| Adernergic Synapse |350px]]  
[[Image:B2AR-Adernergic synapse.JPG|right|thumb|alt= Alt text| Adernergic Synapse |350px]]
[[Image:B2AR-Norepinephrine.JPG|right|thumb|alt= Alt text| Norephrine |250px]]




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NE binds to adrenergic receptors embedded in the postsynaptic effector cell membrane.
NE binds to adrenergic receptors embedded in the postsynaptic effector cell membrane.
Following binding of NE, to either alpha or beta receptors,  conformational changes in the receptor lead to a disassociation of the G protein from the cytoplasmic face of the receptor which activates a second messenger, initiating a signaling cascade.
Following binding of NE, to either alpha or beta receptors,  conformational changes in the receptor lead to a disassociation of the G protein from the cytoplasmic face of the receptor which activates a second messenger, initiating a signaling cascade.
[[Image:B2AR-Norepinephrine.JPG|thumb|alt= Alt text| Norephrine|250px]]
 




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{| border="1" cellpadding="2"
{| border="1" cellpadding="2"
! scope="col" width="50" | Name
! scope="col" width="50" | Name
! scope="col" width="175" | Description
! scope="col" width="150" | Description
! scope="col" width="350" | Chemical Structure
! scope="col" width="250" | Chemical Structure
! scope="col" width="350" | Photo
! scope="col" width="250" | Photo
|-
|-
| Isoproterenol || Isoproterenol is an agonist that is structurally similar to NE and readily binds to B2AR with high affinity. Isoproterenol contains  an isopropyl amine group and a catechol group. || [[Image:B2AR-Isoproterenol-Structure.JPG|thumb|center|alt= Alt text| |350px]]  || [[Image:Isoproterenol-Picture.JPG|thumb|center|alt= Alt text| |300px]]  
| Isoproterenol || Isoproterenol is an agonist that is structurally similar to NE and readily binds to B2AR with high affinity. Isoproterenol contains  an isopropyl amine group and a catechol group. || [[Image:B2AR-Isoproterenol-Structure.JPG|thumb|center|alt= Alt text| |300px]]  || [[Image:Isoproterenol-Picture.JPG|thumb|center|alt= Alt text| |250px]]  
|-
|-
| BI-167107 || The active state of B2AR was crystallized using BI-1671071 . Although it is not a catecholamine, it is a full agonist. || [[Image:B2AR-BI-167107-Structure.JPG|thumb|center|alt= Alt text| |350px]] || [[Image:B2AR-BI-167107-Picture.JPG|thumb|center|alt= Alt text| |300px]]
| BI-167107 || The active state of B2AR was crystallized using BI-1671071 . Although it is not a catecholamine, it is a full agonist. || [[Image:B2AR-BI-167107-Structure.JPG|thumb|center|alt= Alt text| |300px]] || [[Image:B2AR-BI-167107-Picture.JPG|thumb|center|alt= Alt text| |250px]]
|-
|-
| Carazolol || Carazolol is an inverse agonist designed to inhibit B₂AR. Carazolol contains a propylamine and a carbazole group. || [[Image:B2AR-Carazolol-structure.JPG|thumb|center|alt= Alt text| |300px]] ||  [[Image:B2AR-Carazolol-Picture.JPG|thumb|center|alt= Alt text| |300px]]
| Carazolol || Carazolol is an inverse agonist designed to inhibit B₂AR. Carazolol contains a propylamine and a carbazole group. || [[Image:B2AR-Carazolol-structure.JPG|thumb|center|alt= Alt text| |250px]] ||  [[Image:B2AR-Carazolol-Picture.JPG|thumb|center|alt= Alt text| |250px]]
|}
|}


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These are common characteristics of B₂AR antagonists.
These are common characteristics of B₂AR antagonists.
----


==='''Ligand Binding'''===


<applet load='3P0G' size='300' frame='true' align='right' scene='Sandbox_121/B2ar_struc/1' caption='B₂AR active state in complex with BI-167107'/>
<applet load='3P0G' size='300' frame='true' align='right' scene='Sandbox_121/B2ar_struc/1' caption='B₂AR active state in complex with BI-167107'/>


<applet load='2RH1' size='300' frame='true' align='left' scene='Sandbox_121/2rh1/1' caption='B₂AR inactive state in complex with Carazolol'/>
<applet load='2RH1' size='300' frame='true' align='right' scene='Sandbox_121/2rh1/1' caption='B₂AR inactive state in complex with Carazolol'/>
 


==='''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.  


Inactive B₂AR in complex with Carazolol: <scene name='Sandbox_121/2rh1/2'>Polar</scene> and <scene name='Sandbox_121/2rh1/3'>Hydrophobic</scene> Interactions
Inactive B₂AR in complex with Carazolol: <scene name='Sandbox_121/2rh1/2'>Polar</scene> and <scene name='Sandbox_121/2rh1/3'>Hydrophobic</scene> Interactions
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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
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


[[Image:B2AR_Binding_Pocket_PolarInt_Act_In.JPG|left|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. |425px]]


{{clear}}
{{clear}}


==='''Conformational Change'''===
==='''Conformational Change'''===
[[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. |300px]]
[[Image:B2AR-Binding_Pocket_clash.JPG|thumb|right|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. |300px]]
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.  
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.  
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.  
{{clear}}
==='''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.
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