2om9: Difference between revisions

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==Overview==

Ajulemic acid (AJA) is a synthetic analog of THC-11-oic acid, a metabolite, of tetrahydrocannabinol (THC), the major active ingredient of the, recreational drug marijuana derived from the plant Cannabis sativa. AJA, has potent analgesic and anti-inflammatory activity in vivo, but without, the psychotropic action of THC. However, its precise mechanism of action, remains unknown. Biochemical studies indicate that AJA binds directly and, selectively to the isotype gamma of the peroxisome proliferator-activated, receptor (PPARgamma) suggesting that this may be a pharmacologically, relevant receptor for this compound and a potential target for drug, development in the treatment of pain and inflammation. Here, we report the, crystal structure of the ligand binding domain of the gamma isotype of, human PPAR in complex with ajulemic acid, determined at 2.8-A resolution., Our results show a binding mode that is compatible with other known, partial agonists of PPAR, explaining their moderate activation of the, receptor, as well as the structural basis for isotype selectivity, as, observed previously in vitro. The structure also provides clues to the, understanding of partial agonism itself, suggesting a rational approach to, the design of molecules capable of activating the receptor at levels that, avoid undesirable side effects.

Ajulemic acid (AJA) is a synthetic analog of THC-11-oic acid, a metabolite of tetrahydrocannabinol (THC), the major active ingredient of the recreational drug marijuana derived from the plant Cannabis sativa. AJA has potent analgesic and anti-inflammatory activity in vivo, but without the psychotropic action of THC. However, its precise mechanism of action remains unknown. Biochemical studies indicate that AJA binds directly and selectively to the isotype gamma of the peroxisome proliferator-activated receptor (PPARgamma) suggesting that this may be a pharmacologically relevant receptor for this compound and a potential target for drug development in the treatment of pain and inflammation. Here, we report the crystal structure of the ligand binding domain of the gamma isotype of human PPAR in complex with ajulemic acid, determined at 2.8-A resolution. Our results show a binding mode that is compatible with other known partial agonists of PPAR, explaining their moderate activation of the receptor, as well as the structural basis for isotype selectivity, as observed previously in vitro. The structure also provides clues to the understanding of partial agonism itself, suggesting a rational approach to the design of molecules capable of activating the receptor at levels that avoid undesirable side effects.

==Disease==

Known diseases associated with this structure: Abdominal body fat distribution, modifier of OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=601487 601487]], Diabetes mellitus, insulin-resistant, with acanthosis nigricans and hypertension OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=601487 601487]], Glioblastoma, susceptibility to OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=601487 601487]], Insulin resistance, severe, digenic OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=601487 601487]], Lipodystrophy, familial partial OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=601487 601487]], Obesity, resistance to OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=601487 601487]], Obesity, severe OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=601487 601487]]

==About this Structure==

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[[Category: Homo sapiens]]

[[Category: Single protein]]

[[Category: Ambrosio, A.L.B.]]

[[Category: Ambrosio, A L.B.]]

[[Category: Garratt, R.C.]]

[[Category: Garratt, R C.]]

[[Category: AJA]]

[[Category: ajulemic acid]]

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[[Category: ppar gamma]]

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@@ Line 4: / Line 4: @@
 ==Overview==
-Ajulemic acid (AJA) is a synthetic analog of THC-11-oic acid, a metabolite, of tetrahydrocannabinol (THC), the major active ingredient of the, recreational drug marijuana derived from the plant Cannabis sativa. AJA, has potent analgesic and anti-inflammatory activity in vivo, but without, the psychotropic action of THC. However, its precise mechanism of action, remains unknown. Biochemical studies indicate that AJA binds directly and, selectively to the isotype gamma of the peroxisome proliferator-activated, receptor (PPARgamma) suggesting that this may be a pharmacologically, relevant receptor for this compound and a potential target for drug, development in the treatment of pain and inflammation. Here, we report the, crystal structure of the ligand binding domain of the gamma isotype of, human PPAR in complex with ajulemic acid, determined at 2.8-A resolution., Our results show a binding mode that is compatible with other known, partial agonists of PPAR, explaining their moderate activation of the, receptor, as well as the structural basis for isotype selectivity, as, observed previously in vitro. The structure also provides clues to the, understanding of partial agonism itself, suggesting a rational approach to, the design of molecules capable of activating the receptor at levels that, avoid undesirable side effects.
+Ajulemic acid (AJA) is a synthetic analog of THC-11-oic acid, a metabolite of tetrahydrocannabinol (THC), the major active ingredient of the recreational drug marijuana derived from the plant Cannabis sativa. AJA has potent analgesic and anti-inflammatory activity in vivo, but without the psychotropic action of THC. However, its precise mechanism of action remains unknown. Biochemical studies indicate that AJA binds directly and selectively to the isotype gamma of the peroxisome proliferator-activated receptor (PPARgamma) suggesting that this may be a pharmacologically relevant receptor for this compound and a potential target for drug development in the treatment of pain and inflammation. Here, we report the crystal structure of the ligand binding domain of the gamma isotype of human PPAR in complex with ajulemic acid, determined at 2.8-A resolution. Our results show a binding mode that is compatible with other known partial agonists of PPAR, explaining their moderate activation of the receptor, as well as the structural basis for isotype selectivity, as observed previously in vitro. The structure also provides clues to the understanding of partial agonism itself, suggesting a rational approach to the design of molecules capable of activating the receptor at levels that avoid undesirable side effects.
+==Disease==
+Known diseases associated with this structure: Abdominal body fat distribution, modifier of OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=601487 601487]], Diabetes mellitus, insulin-resistant, with acanthosis nigricans and hypertension OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=601487 601487]], Glioblastoma, susceptibility to OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=601487 601487]], Insulin resistance, severe, digenic OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=601487 601487]], Lipodystrophy, familial partial OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=601487 601487]], Obesity, resistance to OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=601487 601487]], Obesity, severe OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=601487 601487]]
 ==About this Structure==
@@ Line 13: / Line 16: @@
 [[Category: Homo sapiens]]
 [[Category: Single protein]]
-[[Category: Ambrosio, A.L.B.]]
+[[Category: Ambrosio, A L.B.]]
-[[Category: Garratt, R.C.]]
+[[Category: Garratt, R C.]]
 [[Category: AJA]]
 [[Category: ajulemic acid]]
@@ Line 21: / Line 24: @@
 [[Category: ppar gamma]]
-''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Wed Jan 23 14:22:58 2008''
+''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 18:20:03 2008''