Adenylyl cyclase is the enzyme that converts ATP to cAMP. Cells can customize their cAMP signaling system by synthesizing up to nine different types of adenylyl cyclase. The adenylyl cyclase enzyme is made up of a cytosolic N-terminal domain (C1) followed by two transmembrane clusters (each made up of 6 helices) followed finally by a cytosolic C-terminal domain (C2). Shown here are the two cytosolic domains C1 and C2 embody the regulatory capabilities of adenylyl cyclase. Their structures are very similar. Both consist of 6 alpha helices and 9 beta strands. C1 has three beta sheets (one with 2 strands, one with 3 strands, and one with 4 strands) . C2 has two beta sheets (one with 7 strands and one with 2 strands). P-SITE INHIBITORS Adenylyl cyclase is inhibited by adenosine analogs known as P-site inhibitors. These noncompetitive inhibitors only bind when pyrophosphate and either Mg or Mn are present. Pyrophosphate is bound by: Arg484, Arg1029, and Lys1065 The P-site and the substrate (ATP) binding site are the same. This site is formed by: Asp396, Ile397, and Asp440 The P-site inhibitors form a hydrogen bond with the pyrophosphate and Asp440. The first C1 alpha helix serves as a lid for the active site and closes upon substrate binding. Arg1029 and Asn1025 are two residues essential for catalytic activation. Arg1029 stabilizes the reaction intermediate. Asn1025 is important for the conformational change that occurs upon ligand binding. Effects of Forskolin Adenylyl cyclase is stimulated by the forskolin (a diterpene) and by the heterotrimeric G-protein. Forskolin stabilizes the association between the two cytosolic domains resulting in the formation of an active site. The forskolin-binding site is adjacent to the G-protein (alpha subunit) binding site. The residues that make up the forskolin binding site are: From C1: Phe394, Trp507, Val511, and Tyr443 From C2: Lys896, Ile940, Gly941, and Ser942. G-PROTEIN The stimulatory G-protein acts as an allosteric activator of adenylyl cyclase. Binding of the alpha subunit to adenylyl cyclase induces a conformational change which primes the active site for catalysis. The G-protein inserts its switch II helix into the groove formed by the third C2 helix and the loop between the first two C2 helices. By inserting this helix, it widens the cleft, causing the loop between the first two C2 helices to rotate away from the C1 core. This forces the C1 core to rotate 7 degrees. You may wish to manipulate this image yourself: Click and hold the left mouse button to rotate the image about the x and y axes. Rotate about the z axis by pressing the shift key and right mouse button together. The image may be translated along the x and y axes by pressing control and the right mouse button. By pressing shift and the left mouse button together, you may zoom the image in or out. Clicking the right mouse button on the image gives a menu which offers several choices, including spinning the image and changing the appearance and color of the molecule. For more information on this adenylyl cyclase, consult: Tesmer, J. et al. (1997) Science 278: 1907-1916.
C1 and C2 embody the regulatory capabilities of adenylyl cyclase. Their structures are very similar. Both consist of 6 alpha helices and 9 beta strands. C1 has three beta sheets (one with 2 strands, one with 3 strands, and one with 4 strands) . C2 has two beta sheets (one with 7 strands and one with 2 strands). P-SITE INHIBITORS Adenylyl cyclase is inhibited by adenosine analogs known as P-site inhibitors. These noncompetitive inhibitors only bind when pyrophosphate and either Mg or Mn are present. Pyrophosphate is bound by: Arg484, Arg1029, and Lys1065 The P-site and the substrate (ATP) binding site are the same. This site is formed by: Asp396, Ile397, and Asp440 The P-site inhibitors form a hydrogen bond with the pyrophosphate and Asp440. The first C1 alpha helix serves as a lid for the active site and closes upon substrate binding. Arg1029 and Asn1025 are two residues essential for catalytic activation. Arg1029 stabilizes the reaction intermediate. Asn1025 is important for the conformational change that occurs upon ligand binding. Effects of Forskolin Adenylyl cyclase is stimulated by the forskolin (a diterpene) and by the heterotrimeric G-protein. Forskolin stabilizes the association between the two cytosolic domains resulting in the formation of an active site. The forskolin-binding site is adjacent to the G-protein (alpha subunit) binding site. The residues that make up the forskolin binding site are: From C1: Phe394, Trp507, Val511, and Tyr443 From C2: Lys896, Ile940, Gly941, and Ser942. G-PROTEIN The stimulatory G-protein acts as an allosteric activator of adenylyl cyclase. Binding of the alpha subunit to adenylyl cyclase induces a conformational change which primes the active site for catalysis. The G-protein inserts its switch II helix into the groove formed by the third C2 helix and the loop between the first two C2 helices. By inserting this helix, it widens the cleft, causing the loop between the first two C2 helices to rotate away from the C1 core. This forces the C1 core to rotate 7 degrees. You may wish to manipulate this image yourself: Click and hold the left mouse button to rotate the image about the x and y axes. Rotate about the z axis by pressing the shift key and right mouse button together. The image may be translated along the x and y axes by pressing control and the right mouse button. By pressing shift and the left mouse button together, you may zoom the image in or out. Clicking the right mouse button on the image gives a menu which offers several choices, including spinning the image and changing the appearance and color of the molecule. For more information on this adenylyl cyclase, consult: Tesmer, J. et al. (1997) Science 278: 1907-1916.
C1 has three beta sheets (one with 2 strands, one with 3 strands, and one with 4 strands) . C2 has two beta sheets (one with 7 strands and one with 2 strands). P-SITE INHIBITORS Adenylyl cyclase is inhibited by adenosine analogs known as P-site inhibitors. These noncompetitive inhibitors only bind when pyrophosphate and either Mg or Mn are present. Pyrophosphate is bound by: Arg484, Arg1029, and Lys1065 The P-site and the substrate (ATP) binding site are the same. This site is formed by: Asp396, Ile397, and Asp440 The P-site inhibitors form a hydrogen bond with the pyrophosphate and Asp440. The first C1 alpha helix serves as a lid for the active site and closes upon substrate binding. Arg1029 and Asn1025 are two residues essential for catalytic activation. Arg1029 stabilizes the reaction intermediate. Asn1025 is important for the conformational change that occurs upon ligand binding. Effects of Forskolin Adenylyl cyclase is stimulated by the forskolin (a diterpene) and by the heterotrimeric G-protein. Forskolin stabilizes the association between the two cytosolic domains resulting in the formation of an active site. The forskolin-binding site is adjacent to the G-protein (alpha subunit) binding site. The residues that make up the forskolin binding site are: From C1: Phe394, Trp507, Val511, and Tyr443 From C2: Lys896, Ile940, Gly941, and Ser942. G-PROTEIN The stimulatory G-protein acts as an allosteric activator of adenylyl cyclase. Binding of the alpha subunit to adenylyl cyclase induces a conformational change which primes the active site for catalysis. The G-protein inserts its switch II helix into the groove formed by the third C2 helix and the loop between the first two C2 helices. By inserting this helix, it widens the cleft, causing the loop between the first two C2 helices to rotate away from the C1 core. This forces the C1 core to rotate 7 degrees. You may wish to manipulate this image yourself: Click and hold the left mouse button to rotate the image about the x and y axes. Rotate about the z axis by pressing the shift key and right mouse button together. The image may be translated along the x and y axes by pressing control and the right mouse button. By pressing shift and the left mouse button together, you may zoom the image in or out. Clicking the right mouse button on the image gives a menu which offers several choices, including spinning the image and changing the appearance and color of the molecule. For more information on this adenylyl cyclase, consult: Tesmer, J. et al. (1997) Science 278: 1907-1916.
P-SITE INHIBITORS
Adenylyl cyclase is inhibited by adenosine analogs known as P-site inhibitors. These noncompetitive inhibitors only bind when pyrophosphate and either Mg or Mn are present.
Pyrophosphate is bound by: Arg484, Arg1029, and Lys1065 The P-site and the substrate (ATP) binding site are the same. This site is formed by: Asp396, Ile397, and Asp440 The P-site inhibitors form a hydrogen bond with the pyrophosphate and Asp440. The first C1 alpha helix serves as a lid for the active site and closes upon substrate binding. Arg1029 and Asn1025 are two residues essential for catalytic activation. Arg1029 stabilizes the reaction intermediate. Asn1025 is important for the conformational change that occurs upon ligand binding. Effects of Forskolin Adenylyl cyclase is stimulated by the forskolin (a diterpene) and by the heterotrimeric G-protein. Forskolin stabilizes the association between the two cytosolic domains resulting in the formation of an active site. The forskolin-binding site is adjacent to the G-protein (alpha subunit) binding site. The residues that make up the forskolin binding site are: From C1: Phe394, Trp507, Val511, and Tyr443 From C2: Lys896, Ile940, Gly941, and Ser942. G-PROTEIN The stimulatory G-protein acts as an allosteric activator of adenylyl cyclase. Binding of the alpha subunit to adenylyl cyclase induces a conformational change which primes the active site for catalysis. The G-protein inserts its switch II helix into the groove formed by the third C2 helix and the loop between the first two C2 helices. By inserting this helix, it widens the cleft, causing the loop between the first two C2 helices to rotate away from the C1 core. This forces the C1 core to rotate 7 degrees. You may wish to manipulate this image yourself: Click and hold the left mouse button to rotate the image about the x and y axes. Rotate about the z axis by pressing the shift key and right mouse button together. The image may be translated along the x and y axes by pressing control and the right mouse button. By pressing shift and the left mouse button together, you may zoom the image in or out. Clicking the right mouse button on the image gives a menu which offers several choices, including spinning the image and changing the appearance and color of the molecule. For more information on this adenylyl cyclase, consult: Tesmer, J. et al. (1997) Science 278: 1907-1916.
The P-site and the substrate (ATP) binding site are the same. This site is formed by: Asp396, Ile397, and Asp440 The P-site inhibitors form a hydrogen bond with the pyrophosphate and Asp440. The first C1 alpha helix serves as a lid for the active site and closes upon substrate binding. Arg1029 and Asn1025 are two residues essential for catalytic activation. Arg1029 stabilizes the reaction intermediate. Asn1025 is important for the conformational change that occurs upon ligand binding. Effects of Forskolin Adenylyl cyclase is stimulated by the forskolin (a diterpene) and by the heterotrimeric G-protein. Forskolin stabilizes the association between the two cytosolic domains resulting in the formation of an active site. The forskolin-binding site is adjacent to the G-protein (alpha subunit) binding site. The residues that make up the forskolin binding site are: From C1: Phe394, Trp507, Val511, and Tyr443 From C2: Lys896, Ile940, Gly941, and Ser942. G-PROTEIN The stimulatory G-protein acts as an allosteric activator of adenylyl cyclase. Binding of the alpha subunit to adenylyl cyclase induces a conformational change which primes the active site for catalysis. The G-protein inserts its switch II helix into the groove formed by the third C2 helix and the loop between the first two C2 helices. By inserting this helix, it widens the cleft, causing the loop between the first two C2 helices to rotate away from the C1 core. This forces the C1 core to rotate 7 degrees. You may wish to manipulate this image yourself: Click and hold the left mouse button to rotate the image about the x and y axes. Rotate about the z axis by pressing the shift key and right mouse button together. The image may be translated along the x and y axes by pressing control and the right mouse button. By pressing shift and the left mouse button together, you may zoom the image in or out. Clicking the right mouse button on the image gives a menu which offers several choices, including spinning the image and changing the appearance and color of the molecule. For more information on this adenylyl cyclase, consult: Tesmer, J. et al. (1997) Science 278: 1907-1916.
The P-site inhibitors form a hydrogen bond with the pyrophosphate and Asp440. The first C1 alpha helix serves as a lid for the active site and closes upon substrate binding. Arg1029 and Asn1025 are two residues essential for catalytic activation. Arg1029 stabilizes the reaction intermediate. Asn1025 is important for the conformational change that occurs upon ligand binding. Effects of Forskolin Adenylyl cyclase is stimulated by the forskolin (a diterpene) and by the heterotrimeric G-protein. Forskolin stabilizes the association between the two cytosolic domains resulting in the formation of an active site. The forskolin-binding site is adjacent to the G-protein (alpha subunit) binding site. The residues that make up the forskolin binding site are: From C1: Phe394, Trp507, Val511, and Tyr443 From C2: Lys896, Ile940, Gly941, and Ser942. G-PROTEIN The stimulatory G-protein acts as an allosteric activator of adenylyl cyclase. Binding of the alpha subunit to adenylyl cyclase induces a conformational change which primes the active site for catalysis. The G-protein inserts its switch II helix into the groove formed by the third C2 helix and the loop between the first two C2 helices. By inserting this helix, it widens the cleft, causing the loop between the first two C2 helices to rotate away from the C1 core. This forces the C1 core to rotate 7 degrees. You may wish to manipulate this image yourself: Click and hold the left mouse button to rotate the image about the x and y axes. Rotate about the z axis by pressing the shift key and right mouse button together. The image may be translated along the x and y axes by pressing control and the right mouse button. By pressing shift and the left mouse button together, you may zoom the image in or out. Clicking the right mouse button on the image gives a menu which offers several choices, including spinning the image and changing the appearance and color of the molecule. For more information on this adenylyl cyclase, consult: Tesmer, J. et al. (1997) Science 278: 1907-1916.
The first C1 alpha helix serves as a lid for the active site and closes upon substrate binding. Arg1029 and Asn1025 are two residues essential for catalytic activation. Arg1029 stabilizes the reaction intermediate. Asn1025 is important for the conformational change that occurs upon ligand binding. Effects of Forskolin Adenylyl cyclase is stimulated by the forskolin (a diterpene) and by the heterotrimeric G-protein. Forskolin stabilizes the association between the two cytosolic domains resulting in the formation of an active site. The forskolin-binding site is adjacent to the G-protein (alpha subunit) binding site. The residues that make up the forskolin binding site are: From C1: Phe394, Trp507, Val511, and Tyr443 From C2: Lys896, Ile940, Gly941, and Ser942. G-PROTEIN The stimulatory G-protein acts as an allosteric activator of adenylyl cyclase. Binding of the alpha subunit to adenylyl cyclase induces a conformational change which primes the active site for catalysis. The G-protein inserts its switch II helix into the groove formed by the third C2 helix and the loop between the first two C2 helices. By inserting this helix, it widens the cleft, causing the loop between the first two C2 helices to rotate away from the C1 core. This forces the C1 core to rotate 7 degrees. You may wish to manipulate this image yourself: Click and hold the left mouse button to rotate the image about the x and y axes. Rotate about the z axis by pressing the shift key and right mouse button together. The image may be translated along the x and y axes by pressing control and the right mouse button. By pressing shift and the left mouse button together, you may zoom the image in or out. Clicking the right mouse button on the image gives a menu which offers several choices, including spinning the image and changing the appearance and color of the molecule. For more information on this adenylyl cyclase, consult: Tesmer, J. et al. (1997) Science 278: 1907-1916.
Arg1029 and Asn1025 are two residues essential for catalytic activation. Arg1029 stabilizes the reaction intermediate. Asn1025 is important for the conformational change that occurs upon ligand binding. Effects of Forskolin Adenylyl cyclase is stimulated by the forskolin (a diterpene) and by the heterotrimeric G-protein. Forskolin stabilizes the association between the two cytosolic domains resulting in the formation of an active site. The forskolin-binding site is adjacent to the G-protein (alpha subunit) binding site. The residues that make up the forskolin binding site are: From C1: Phe394, Trp507, Val511, and Tyr443 From C2: Lys896, Ile940, Gly941, and Ser942. G-PROTEIN The stimulatory G-protein acts as an allosteric activator of adenylyl cyclase. Binding of the alpha subunit to adenylyl cyclase induces a conformational change which primes the active site for catalysis. The G-protein inserts its switch II helix into the groove formed by the third C2 helix and the loop between the first two C2 helices. By inserting this helix, it widens the cleft, causing the loop between the first two C2 helices to rotate away from the C1 core. This forces the C1 core to rotate 7 degrees. You may wish to manipulate this image yourself: Click and hold the left mouse button to rotate the image about the x and y axes. Rotate about the z axis by pressing the shift key and right mouse button together. The image may be translated along the x and y axes by pressing control and the right mouse button. By pressing shift and the left mouse button together, you may zoom the image in or out. Clicking the right mouse button on the image gives a menu which offers several choices, including spinning the image and changing the appearance and color of the molecule. For more information on this adenylyl cyclase, consult: Tesmer, J. et al. (1997) Science 278: 1907-1916.
Effects of Forskolin
Adenylyl cyclase is stimulated by the forskolin (a diterpene) and by the heterotrimeric G-protein.
Forskolin stabilizes the association between the two cytosolic domains resulting in the formation of an active site. The forskolin-binding site is adjacent to the G-protein (alpha subunit) binding site. The residues that make up the forskolin binding site are: From C1: Phe394, Trp507, Val511, and Tyr443 From C2: Lys896, Ile940, Gly941, and Ser942. G-PROTEIN The stimulatory G-protein acts as an allosteric activator of adenylyl cyclase. Binding of the alpha subunit to adenylyl cyclase induces a conformational change which primes the active site for catalysis. The G-protein inserts its switch II helix into the groove formed by the third C2 helix and the loop between the first two C2 helices. By inserting this helix, it widens the cleft, causing the loop between the first two C2 helices to rotate away from the C1 core. This forces the C1 core to rotate 7 degrees. You may wish to manipulate this image yourself: Click and hold the left mouse button to rotate the image about the x and y axes. Rotate about the z axis by pressing the shift key and right mouse button together. The image may be translated along the x and y axes by pressing control and the right mouse button. By pressing shift and the left mouse button together, you may zoom the image in or out. Clicking the right mouse button on the image gives a menu which offers several choices, including spinning the image and changing the appearance and color of the molecule. For more information on this adenylyl cyclase, consult: Tesmer, J. et al. (1997) Science 278: 1907-1916.
The forskolin-binding site is adjacent to the G-protein (alpha subunit) binding site. The residues that make up the forskolin binding site are: From C1: Phe394, Trp507, Val511, and Tyr443 From C2: Lys896, Ile940, Gly941, and Ser942. G-PROTEIN The stimulatory G-protein acts as an allosteric activator of adenylyl cyclase. Binding of the alpha subunit to adenylyl cyclase induces a conformational change which primes the active site for catalysis. The G-protein inserts its switch II helix into the groove formed by the third C2 helix and the loop between the first two C2 helices. By inserting this helix, it widens the cleft, causing the loop between the first two C2 helices to rotate away from the C1 core. This forces the C1 core to rotate 7 degrees. You may wish to manipulate this image yourself: Click and hold the left mouse button to rotate the image about the x and y axes. Rotate about the z axis by pressing the shift key and right mouse button together. The image may be translated along the x and y axes by pressing control and the right mouse button. By pressing shift and the left mouse button together, you may zoom the image in or out. Clicking the right mouse button on the image gives a menu which offers several choices, including spinning the image and changing the appearance and color of the molecule. For more information on this adenylyl cyclase, consult: Tesmer, J. et al. (1997) Science 278: 1907-1916.
G-PROTEIN
The stimulatory G-protein acts as an allosteric activator of adenylyl cyclase. Binding of the alpha subunit to adenylyl cyclase induces a conformational change which primes the active site for catalysis. The G-protein inserts its switch II helix into the groove formed by the third C2 helix and the loop between the first two C2 helices. By inserting this helix, it widens the cleft, causing the loop between the first two C2 helices to rotate away from the C1 core. This forces the C1 core to rotate 7 degrees. You may wish to manipulate this image yourself: Click and hold the left mouse button to rotate the image about the x and y axes. Rotate about the z axis by pressing the shift key and right mouse button together. The image may be translated along the x and y axes by pressing control and the right mouse button. By pressing shift and the left mouse button together, you may zoom the image in or out. Clicking the right mouse button on the image gives a menu which offers several choices, including spinning the image and changing the appearance and color of the molecule. For more information on this adenylyl cyclase, consult: Tesmer, J. et al. (1997) Science 278: 1907-1916.
The G-protein inserts its switch II helix into the groove formed by the third C2 helix and the loop between the first two C2 helices. By inserting this helix, it widens the cleft, causing the loop between the first two C2 helices to rotate away from the C1 core. This forces the C1 core to rotate 7 degrees. You may wish to manipulate this image yourself: Click and hold the left mouse button to rotate the image about the x and y axes. Rotate about the z axis by pressing the shift key and right mouse button together. The image may be translated along the x and y axes by pressing control and the right mouse button. By pressing shift and the left mouse button together, you may zoom the image in or out. Clicking the right mouse button on the image gives a menu which offers several choices, including spinning the image and changing the appearance and color of the molecule.
By inserting this helix, it widens the cleft, causing the loop between the first two C2 helices to rotate away from the C1 core. This forces the C1 core to rotate 7 degrees.
You may wish to manipulate this image yourself:
For more information on this adenylyl cyclase, consult: Tesmer, J. et al. (1997) Science 278: 1907-1916.