Sandbox 121: Difference between revisions

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==='''~~Agonists~~'''===

==='''Structure of Beta 2 Adrenergic Receptor'''===

B2AR is a single chain that crosses the lipid membrane 7 times from the extracellular to cytoplasmic surface. There are 3 extracellular loops and 3 intracellular loops.1

The binding pocket is located to the center of the extracellular surface.

==='''Ligands'''===

To understand activation of B₂AR by various ligands, it is first essential to define the term baseline activity. In the absence of a ligand within the binding pocket, there is some basal activity between the receptor and its signaling pathway. This activity is not considered an active state of the receptor but simply the baseline activity of the receptor. There are two extremes to the activity of the receptor that can be seen with binding of either an inverse agonist or an agonist. The inverse agonist completely stops the basal activity of the receptor whereas the agonist activates the receptor to its maximum.

A ligand that is an antagonist actually has no effect on the basal activity of the receptor. An antagonist simply sterically blocks the receptor so that no other ligand can bind. Their activity would be considered baseline. Antagonists for the adrenergic receptors are commonly called Beta Blockers. Although Beta Blockers are not prescribed for B₂AR, they are frequently prescribed for Beta-1 Adrenergic Receptors in people with heart conditions.

===='''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.

===='''BI-167107'''====

The active state of B2AR was crystallized using BI- 1671071 . Although it is not a catecholamine, it is a full agonist.

===='''Carazol'''====

Carazolol is an inverse agonist designed to inhibit B₂AR.

Carazolol contains a propylamine and a carbazole group.

===='''Comparison of the Inverse Agonist and the Agonist'''====

Notable differences between carazolol and both isoproterenol and the natural agonist are that:

(i) Carazolol lacks the hydroxyl groups thought necessary for the activation of B₂AR.

(ii) Carazolol is one carbon longer in length from the amine group to the carbazole.

These are common characteristics of B₂AR antagonists.

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

Ligands share several key interactions in the binding pocket including:

(i)Polar interactions between:

The amine and Asp113 in TM3, Asn312 in TM7, and Tyr316 in TM7.

Hydroxyls and other h-bond donors and Ser207 in TM5, Ser203 in TM5, and Asn293 in TM6.

(ii) Hydrophobic interaction between ligand and Val117 in TM3, Phe193

in ECL2, Phe289 in TM6, and Phe290 inTM6.

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@@ Line 26: / Line 26: @@
-==='''Agonists'''===
+==='''Structure of Beta 2 Adrenergic Receptor'''===
+B2AR is a single chain that crosses the lipid membrane 7 times from the extracellular to cytoplasmic surface. There are 3 extracellular loops and 3 intracellular loops.1
+The binding pocket is located to the center of the extracellular surface.
+==='''Ligands'''===
+To understand activation of B₂AR by various ligands, it is first essential to define the term baseline activity. In the absence of a ligand within the binding pocket, there is some basal activity between the receptor and its signaling pathway. This activity is not considered an active state of the receptor but simply the baseline activity of the receptor. There are two extremes to the activity of the receptor that can be seen with binding of either an inverse agonist or an agonist. The inverse agonist completely stops the basal activity of the receptor whereas the agonist activates the receptor to its maximum.
+A ligand that is an antagonist actually has no effect on the basal activity of the receptor.  An antagonist simply sterically blocks the receptor so that no other ligand can bind. Their activity would be considered baseline.  Antagonists for the adrenergic receptors are commonly called Beta Blockers.  Although Beta Blockers are not prescribed for B₂AR, they are frequently prescribed for Beta-1 Adrenergic Receptors in people with heart conditions.
+===='''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.
+===='''BI-167107'''====
+The active state of B2AR was crystallized using BI- 1671071 . Although it is not a catecholamine, it is a full agonist.
+===='''Carazol'''====
+Carazolol is an inverse agonist designed to inhibit B₂AR.
+Carazolol contains a propylamine and a carbazole group.
+===='''Comparison of the Inverse Agonist and the Agonist'''====
+Notable differences between carazolol and both  isoproterenol and the natural agonist are that:
+(i) Carazolol lacks the hydroxyl groups thought necessary for the activation of B₂AR.
+(ii) Carazolol is one carbon longer in length from the amine group to the carbazole.
+These are common characteristics of B₂AR antagonists.
+==='''Ligand Binding'''===
+Ligands share several key interactions in the binding pocket including:
+(i)Polar interactions between:
+The amine and Asp113 in TM3, Asn312 in TM7, and Tyr316 in TM7.
+Hydroxyls and other h-bond donors and Ser207 in TM5, Ser203 in TM5, and Asn293 in TM6.
+(ii) Hydrophobic interaction between ligand and Val117 in TM3, Phe193
+in ECL2, Phe289 in TM6, and Phe290 inTM6.