1s2a: Difference between revisions

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[[Image:1s2a.gif|left|200px]]<br />

[[Image:1s2a.gif|left|200px]]<br /><applet load="1s2a" size="350" color="white" frame="true" align="right" spinBox="true"

<applet load="1s2a" size="~~450~~" color="white" frame="true" align="right" spinBox="true"

caption="1s2a, resolution 1.70Å" />

'''Crystal structures of prostaglandin D2 11-ketoreductase in complex with the non-steroidal anti-inflammatory drugs flufenamic acid and indomethacin'''<br />

==Overview==

It is becoming increasingly well established that nonsteroidal, anti-inflammatory drugs (NSAID) protect against tumors of the, gastrointestinal tract and that they may also protect against a variety of, other tumors. These activities have been widely attributed to the, inhibition of cylooxygenases (COX) and, in particular, COX-2. However, several observations have indicated that other targets may be involved., Besides targeting COX, certain NSAID also inhibit enzymes belonging to the, aldo-keto reductase (AKR) family, including AKR1C3. We have demonstrated, previously that overexpression of AKR1C3 acts to suppress cell, differentiation and promote proliferation in myeloid cells. However, this, enzyme has a broad tissue distribution and therefore represents a novel, candidate for the target of the COX-independent antineoplastic actions of, NSAID. Here we report on the X-ray crystal structures of AKR1C3 complexed, with the NSAID indomethacin (1.8 A resolution) or flufenamic acid (1.7 A, resolution). One molecule of indomethacin is bound in the active site, whereas flufenamic acid binds to both the active site and the beta-hairpin, loop, at the opposite end of the central beta-barrel. Two other crystal, structures (1.20 and 2.1 A resolution) show acetate bound in the active, site occupying the proposed oxyanion hole. The data underline AKR1C3 as a, COX-independent target for NSAID and will provide a structural basis for, the future development of new cancer therapies with reduced COX-dependent, side effects.

It is becoming increasingly well established that nonsteroidal anti-inflammatory drugs (NSAID) protect against tumors of the gastrointestinal tract and that they may also protect against a variety of other tumors. These activities have been widely attributed to the inhibition of cylooxygenases (COX) and, in particular, COX-2. However, several observations have indicated that other targets may be involved. Besides targeting COX, certain NSAID also inhibit enzymes belonging to the aldo-keto reductase (AKR) family, including AKR1C3. We have demonstrated previously that overexpression of AKR1C3 acts to suppress cell differentiation and promote proliferation in myeloid cells. However, this enzyme has a broad tissue distribution and therefore represents a novel candidate for the target of the COX-independent antineoplastic actions of NSAID. Here we report on the X-ray crystal structures of AKR1C3 complexed with the NSAID indomethacin (1.8 A resolution) or flufenamic acid (1.7 A resolution). One molecule of indomethacin is bound in the active site, whereas flufenamic acid binds to both the active site and the beta-hairpin loop, at the opposite end of the central beta-barrel. Two other crystal structures (1.20 and 2.1 A resolution) show acetate bound in the active site occupying the proposed oxyanion hole. The data underline AKR1C3 as a COX-independent target for NSAID and will provide a structural basis for the future development of new cancer therapies with reduced COX-dependent side effects.

==About this Structure==

1S2A is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with NAP, IMN, DMS and UNX as [http://en.wikipedia.org/wiki/ligands ligands]. Full crystallographic information is available from [http://~~ispc~~.weizmann.ac.il/oca-bin/ocashort?id=1S2A OCA].

1S2A is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with <scene name='pdbligand=NAP:'>NAP</scene>, <scene name='pdbligand=IMN:'>IMN</scene>, <scene name='pdbligand=DMS:'>DMS</scene> and <scene name='pdbligand=UNX:'>UNX</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1S2A OCA].

==Reference==

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[[Category: Homo sapiens]]

[[Category: Single protein]]

[[Category: Bunce, C.M.]]

[[Category: Bunce, C M.]]

[[Category: Cummings, S.M.]]

[[Category: Cummings, S M.]]

[[Category: Desmond, J.C.]]

[[Category: Desmond, J C.]]

[[Category: Lovering, A.L.]]

[[Category: Lovering, A L.]]

[[Category: Ride, J.P.]]

[[Category: Ride, J P.]]

[[Category: White, S.A.]]

[[Category: White, S A.]]

[[Category: DMS]]

[[Category: IMN]]

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[[Category: tim-barrel]]

''Page seeded by [http://~~ispc~~.weizmann.ac.il/oca OCA ] on ~~Mon Nov 12 19~~:09:~~37 2007~~''

''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 14:57:12 2008''

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@@ Line 1: / Line 1: @@
-[[Image:1s2a.gif|left|200px]]<br />
+[[Image:1s2a.gif|left|200px]]<br /><applet load="1s2a" size="350" color="white" frame="true" align="right" spinBox="true"
-<applet load="1s2a" size="450" color="white" frame="true" align="right" spinBox="true"
 caption="1s2a, resolution 1.70&Aring;" />
 '''Crystal structures of prostaglandin D2 11-ketoreductase in complex with the non-steroidal anti-inflammatory drugs flufenamic acid and indomethacin'''<br />
 ==Overview==
-It is becoming increasingly well established that nonsteroidal, anti-inflammatory drugs (NSAID) protect against tumors of the, gastrointestinal tract and that they may also protect against a variety of, other tumors. These activities have been widely attributed to the, inhibition of cylooxygenases (COX) and, in particular, COX-2. However, several observations have indicated that other targets may be involved., Besides targeting COX, certain NSAID also inhibit enzymes belonging to the, aldo-keto reductase (AKR) family, including AKR1C3. We have demonstrated, previously that overexpression of AKR1C3 acts to suppress cell, differentiation and promote proliferation in myeloid cells. However, this, enzyme has a broad tissue distribution and therefore represents a novel, candidate for the target of the COX-independent antineoplastic actions of, NSAID. Here we report on the X-ray crystal structures of AKR1C3 complexed, with the NSAID indomethacin (1.8 A resolution) or flufenamic acid (1.7 A, resolution). One molecule of indomethacin is bound in the active site, whereas flufenamic acid binds to both the active site and the beta-hairpin, loop, at the opposite end of the central beta-barrel. Two other crystal, structures (1.20 and 2.1 A resolution) show acetate bound in the active, site occupying the proposed oxyanion hole. The data underline AKR1C3 as a, COX-independent target for NSAID and will provide a structural basis for, the future development of new cancer therapies with reduced COX-dependent, side effects.
+It is becoming increasingly well established that nonsteroidal anti-inflammatory drugs (NSAID) protect against tumors of the gastrointestinal tract and that they may also protect against a variety of other tumors. These activities have been widely attributed to the inhibition of cylooxygenases (COX) and, in particular, COX-2. However, several observations have indicated that other targets may be involved. Besides targeting COX, certain NSAID also inhibit enzymes belonging to the aldo-keto reductase (AKR) family, including AKR1C3. We have demonstrated previously that overexpression of AKR1C3 acts to suppress cell differentiation and promote proliferation in myeloid cells. However, this enzyme has a broad tissue distribution and therefore represents a novel candidate for the target of the COX-independent antineoplastic actions of NSAID. Here we report on the X-ray crystal structures of AKR1C3 complexed with the NSAID indomethacin (1.8 A resolution) or flufenamic acid (1.7 A resolution). One molecule of indomethacin is bound in the active site, whereas flufenamic acid binds to both the active site and the beta-hairpin loop, at the opposite end of the central beta-barrel. Two other crystal structures (1.20 and 2.1 A resolution) show acetate bound in the active site occupying the proposed oxyanion hole. The data underline AKR1C3 as a COX-independent target for NSAID and will provide a structural basis for the future development of new cancer therapies with reduced COX-dependent side effects.
 ==About this Structure==
-S2A is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with NAP, IMN, DMS and UNX as [http://en.wikipedia.org/wiki/ligands ligands]. Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=1S2A OCA].
+S2A is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with <scene name='pdbligand=NAP:'>NAP</scene>, <scene name='pdbligand=IMN:'>IMN</scene>, <scene name='pdbligand=DMS:'>DMS</scene> and <scene name='pdbligand=UNX:'>UNX</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1S2A OCA].
 ==Reference==
@@ Line 14: / Line 13: @@
 [[Category: Homo sapiens]]
 [[Category: Single protein]]
-[[Category: Bunce, C.M.]]
+[[Category: Bunce, C M.]]
-[[Category: Cummings, S.M.]]
+[[Category: Cummings, S M.]]
-[[Category: Desmond, J.C.]]
+[[Category: Desmond, J C.]]
-[[Category: Lovering, A.L.]]
+[[Category: Lovering, A L.]]
-[[Category: Ride, J.P.]]
+[[Category: Ride, J P.]]
-[[Category: White, S.A.]]
+[[Category: White, S A.]]
 [[Category: DMS]]
 [[Category: IMN]]
@@ Line 26: / Line 25: @@
 [[Category: tim-barrel]]
-''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Mon Nov 12 19:09:37 2007''
+''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 14:57:12 2008''