1adb: Difference between revisions

Revision as of 12:43, 21 February 2008

CRYSTALLOGRAPHIC STUDIES OF ISOSTERIC NAD ANALOGUES BOUND TO ALCOHOL DEHYDROGENASE: SPECIFICITY AND SUBSTRATE BINDING IN TWO TERNARY COMPLEXES

OverviewOverview

CNAD (5-beta-D-ribofuranosylnicotinamide adenine dinucleotide) is an isosteric C-glycosidic analogue of NAD(H) containing a neutral pyridine ring. CPAD (5-beta-D-ribofuranosylpicolinamide adenine dinucleotide) is a closely related pyridine-containing analogue with the pyridine nitrogen on the opposite side of the ring. CNAD is a potent and specific inhibitor of horse liver alcohol dehydrogenase (LADH), binding with a dissociation constant in the nanomolar range. CPAD binds LADH with an affinity comparable to that of NAD. Crystal structures of CNAD and CPAD bound to LADH are presented at 2.4 and 2.7 A, respectively. The two complexes are isomorphous, crystallizing in the triclinic system with cell dimensions different from those seen in previous ternary LADH complexes. Structures were solved using the molecular replacement method and refined to crystallographic R values of 18% (CNAD) and 17% (CPAD). Both inhibitors bind to the "closed" form of LADH in the normal cofactor-binding cleft. The conformation of LADH-bound CPAD closely mimics that of LADH-bound NAD(H). The data suggest that alcohol substrate binds directly to the catalytic zinc atom. In the CNAD complex, the pyridine nitrogen replaces alcohol as the fourth coordination ligand to the active site zinc atom, while all other polar interactions remain the same as those of bound NAD(H). The zinc-nitrogen ligand explains the high affinity of CNAD for LADH.

About this StructureAbout this Structure

1ADB is a Single protein structure of sequence from Equus caballus with , and as ligands. Active as Alcohol dehydrogenase, with EC number 1.1.1.1 Full crystallographic information is available from OCA.

ReferenceReference

Crystallographic studies of isosteric NAD analogues bound to alcohol dehydrogenase: specificity and substrate binding in two ternary complexes., Li H, Hallows WH, Punzi JS, Pankiewicz KW, Watanabe KA, Goldstein BM, Biochemistry. 1994 Oct 4;33(39):11734-44. PMID:7918390

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-[[Image:1adb.gif|left|200px]]<br /><applet load="1adb" size="450" color="white" frame="true" align="right" spinBox="true"
+[[Image:1adb.gif|left|200px]]<br /><applet load="1adb" size="350" color="white" frame="true" align="right" spinBox="true"
 caption="1adb, resolution 2.4&Aring;" />
 '''CRYSTALLOGRAPHIC STUDIES OF ISOSTERIC NAD ANALOGUES BOUND TO ALCOHOL DEHYDROGENASE: SPECIFICITY AND SUBSTRATE BINDING IN TWO TERNARY COMPLEXES'''<br />
 ==Overview==
-CNAD (5-beta-D-ribofuranosylnicotinamide adenine dinucleotide) is an, isosteric C-glycosidic analogue of NAD(H) containing a neutral pyridine, ring. CPAD (5-beta-D-ribofuranosylpicolinamide adenine dinucleotide) is a, closely related pyridine-containing analogue with the pyridine nitrogen on, the opposite side of the ring. CNAD is a potent and specific inhibitor of, horse liver alcohol dehydrogenase (LADH), binding with a dissociation, constant in the nanomolar range. CPAD binds LADH with an affinity, comparable to that of NAD. Crystal structures of CNAD and CPAD bound to, LADH are presented at 2.4 and 2.7 A, respectively. The two complexes are, isomorphous, crystallizing in the triclinic system with cell dimensions, different from those seen in previous ternary LADH complexes. Structures, were solved using the molecular replacement method and refined to, crystallographic R values of 18% (CNAD) and 17% (CPAD). Both inhibitors, bind to the "closed" form of LADH in the normal cofactor-binding cleft., The conformation of LADH-bound CPAD closely mimics that of LADH-bound, NAD(H). The data suggest that alcohol substrate binds directly to the, catalytic zinc atom. In the CNAD complex, the pyridine nitrogen replaces, alcohol as the fourth coordination ligand to the active site zinc atom, while all other polar interactions remain the same as those of bound, NAD(H). The zinc-nitrogen ligand explains the high affinity of CNAD for, LADH.
+CNAD (5-beta-D-ribofuranosylnicotinamide adenine dinucleotide) is an isosteric C-glycosidic analogue of NAD(H) containing a neutral pyridine ring. CPAD (5-beta-D-ribofuranosylpicolinamide adenine dinucleotide) is a closely related pyridine-containing analogue with the pyridine nitrogen on the opposite side of the ring. CNAD is a potent and specific inhibitor of horse liver alcohol dehydrogenase (LADH), binding with a dissociation constant in the nanomolar range. CPAD binds LADH with an affinity comparable to that of NAD. Crystal structures of CNAD and CPAD bound to LADH are presented at 2.4 and 2.7 A, respectively. The two complexes are isomorphous, crystallizing in the triclinic system with cell dimensions different from those seen in previous ternary LADH complexes. Structures were solved using the molecular replacement method and refined to crystallographic R values of 18% (CNAD) and 17% (CPAD). Both inhibitors bind to the "closed" form of LADH in the normal cofactor-binding cleft. The conformation of LADH-bound CPAD closely mimics that of LADH-bound NAD(H). The data suggest that alcohol substrate binds directly to the catalytic zinc atom. In the CNAD complex, the pyridine nitrogen replaces alcohol as the fourth coordination ligand to the active site zinc atom, while all other polar interactions remain the same as those of bound NAD(H). The zinc-nitrogen ligand explains the high affinity of CNAD for LADH.
 ==About this Structure==
-ADB is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Equus_caballus Equus caballus] with ZN, CND and EOH as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Alcohol_dehydrogenase Alcohol dehydrogenase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.1.1.1 1.1.1.1] Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=1ADB OCA].
+ADB is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Equus_caballus Equus caballus] with <scene name='pdbligand=ZN:'>ZN</scene>, <scene name='pdbligand=CND:'>CND</scene> and <scene name='pdbligand=EOH:'>EOH</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Alcohol_dehydrogenase Alcohol dehydrogenase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.1.1.1 1.1.1.1] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1ADB OCA].
 ==Reference==
@@ Line 14: / Line 14: @@
 [[Category: Equus caballus]]
 [[Category: Single protein]]
-[[Category: Goldstein, B.M.]]
+[[Category: Goldstein, B M.]]
-[[Category: Hallows, W.A.]]
+[[Category: Hallows, W A.]]
 [[Category: Li, H.]]
-[[Category: Pankiewicz, K.W.]]
+[[Category: Pankiewicz, K W.]]
-[[Category: Punzi, J.S.]]
+[[Category: Punzi, J S.]]
-[[Category: Watanabe, K.A.]]
+[[Category: Watanabe, K A.]]
 [[Category: CND]]
 [[Category: EOH]]
@@ Line 25: / Line 25: @@
 [[Category: oxidoreductase (nad(a)-choh(d))]]
-''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Tue Nov 20 10:46:11 2007''
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