1fv0: Difference between revisions

Revision as of 13:42, 21 February 2008

FIRST STRUCTURAL EVIDENCE OF THE INHIBITION OF PHOSPHOLIPASE A2 BY ARISTOLOCHIC ACID: CRYSTAL STRUCTURE OF A COMPLEX FORMED BETWEEN PHOSPHOLIPASE A2 AND ARISTOLOCHIC ACID

OverviewOverview

This is the first structural observation of a plant product showing high affinity for phospholipase A(2) and regulating the synthesis of arachidonic acid, an intermediate in the production of prostaglandins. The crystal structure of a complex formed between Vipera russelli phospholipase A(2) and a plant alkaloid aristolochic acid has been determined and refined to 1.7 A resolution. The structure contains two crystallographically independent molecules of phospholipase A(2) in the form of an asymmetric dimer with one molecule of aristolochic acid bound to one of them specifically. The most significant differences introduced by asymmetric molecular association in the structures of two molecules pertain to the conformations of their calcium binding loops, beta-wings, and the C-terminal regions. These differences are associated with a unique conformational behavior of Trp(31). Trp(31) is located at the entrance of the characteristic hydrophobic channel which works as a passage to the active site residues in the enzyme. In the case of molecule A, Trp(31) is found at the interface of two molecules and it forms a number of hydrophobic interactions with the residues of molecule B. Consequently, it is pulled outwardly, leaving the mouth of the hydrophobic channel wide open. On the other hand, Trp(31) in molecule B is exposed to the surface and moves inwardly due to the polar environment on the molecular surface, thus narrowing the opening of the hydrophobic channel. As a result, the aristolochic acid is bound to molecule A only while the binding site of molecule B is empty. It is noteworthy that the most critical interactions in the binding of aristolochic acid are provided by its OH group which forms two hydrogen bonds, one each with His(48) and Asp(49).

About this StructureAbout this Structure

1FV0 is a Single protein structure of sequence from Daboia russellii pulchella with , , , and as ligands. Full crystallographic information is available from OCA.

ReferenceReference

Structural basis of phospholipase A2 inhibition for the synthesis of prostaglandins by the plant alkaloid aristolochic acid from a 1.7 A crystal structure., Chandra V, Jasti J, Kaur P, Srinivasan A, Betzel Ch, Singh TP, Biochemistry. 2002 Sep 10;41(36):10914-9. PMID:12206661

Page seeded by OCA on Thu Feb 21 12:42:57 2008

Proteopedia Page Contributors and Editors (what is this?)Proteopedia Page Contributors and Editors (what is this?)

OCA

@@ Line 1: / Line 1: @@
-[[Image:1fv0.gif|left|200px]]<br /><applet load="1fv0" size="450" color="white" frame="true" align="right" spinBox="true"
+[[Image:1fv0.gif|left|200px]]<br /><applet load="1fv0" size="350" color="white" frame="true" align="right" spinBox="true"
 caption="1fv0, resolution 1.70&Aring;" />
 '''FIRST STRUCTURAL EVIDENCE OF THE INHIBITION OF PHOSPHOLIPASE A2 BY ARISTOLOCHIC ACID: CRYSTAL STRUCTURE OF A COMPLEX FORMED BETWEEN PHOSPHOLIPASE A2 AND ARISTOLOCHIC ACID'''<br />
 ==Overview==
-This is the first structural observation of a plant product showing high, affinity for phospholipase A(2) and regulating the synthesis of, arachidonic acid, an intermediate in the production of prostaglandins. The, crystal structure of a complex formed between Vipera russelli, phospholipase A(2) and a plant alkaloid aristolochic acid has been, determined and refined to 1.7 A resolution. The structure contains two, crystallographically independent molecules of phospholipase A(2) in the, form of an asymmetric dimer with one molecule of aristolochic acid bound, to one of them specifically. The most significant differences introduced, by asymmetric molecular association in the structures of two molecules, pertain to the conformations of their calcium binding loops, beta-wings, and the C-terminal regions. These differences are associated with a unique, conformational behavior of Trp(31). Trp(31) is located at the entrance of, the characteristic hydrophobic channel which works as a passage to the, active site residues in the enzyme. In the case of molecule A, Trp(31) is, found at the interface of two molecules and it forms a number of, hydrophobic interactions with the residues of molecule B. Consequently, it, is pulled outwardly, leaving the mouth of the hydrophobic channel wide, open. On the other hand, Trp(31) in molecule B is exposed to the surface, and moves inwardly due to the polar environment on the molecular surface, thus narrowing the opening of the hydrophobic channel. As a result, the, aristolochic acid is bound to molecule A only while the binding site of, molecule B is empty. It is noteworthy that the most critical interactions, in the binding of aristolochic acid are provided by its OH group which, forms two hydrogen bonds, one each with His(48) and Asp(49).
+This is the first structural observation of a plant product showing high affinity for phospholipase A(2) and regulating the synthesis of arachidonic acid, an intermediate in the production of prostaglandins. The crystal structure of a complex formed between Vipera russelli phospholipase A(2) and a plant alkaloid aristolochic acid has been determined and refined to 1.7 A resolution. The structure contains two crystallographically independent molecules of phospholipase A(2) in the form of an asymmetric dimer with one molecule of aristolochic acid bound to one of them specifically. The most significant differences introduced by asymmetric molecular association in the structures of two molecules pertain to the conformations of their calcium binding loops, beta-wings, and the C-terminal regions. These differences are associated with a unique conformational behavior of Trp(31). Trp(31) is located at the entrance of the characteristic hydrophobic channel which works as a passage to the active site residues in the enzyme. In the case of molecule A, Trp(31) is found at the interface of two molecules and it forms a number of hydrophobic interactions with the residues of molecule B. Consequently, it is pulled outwardly, leaving the mouth of the hydrophobic channel wide open. On the other hand, Trp(31) in molecule B is exposed to the surface and moves inwardly due to the polar environment on the molecular surface, thus narrowing the opening of the hydrophobic channel. As a result, the aristolochic acid is bound to molecule A only while the binding site of molecule B is empty. It is noteworthy that the most critical interactions in the binding of aristolochic acid are provided by its OH group which forms two hydrogen bonds, one each with His(48) and Asp(49).
 ==About this Structure==
-FV0 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Daboia_russellii_pulchella Daboia russellii pulchella] with SO4, ACT, 9AR, DIO and GOL as [http://en.wikipedia.org/wiki/ligands ligands]. Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=1FV0 OCA].
+FV0 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Daboia_russellii_pulchella Daboia russellii pulchella] with <scene name='pdbligand=SO4:'>SO4</scene>, <scene name='pdbligand=ACT:'>ACT</scene>, <scene name='pdbligand=9AR:'>9AR</scene>, <scene name='pdbligand=DIO:'>DIO</scene> and <scene name='pdbligand=GOL:'>GOL</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1FV0 OCA].
 ==Reference==
@@ Line 17: / Line 17: @@
 [[Category: Jasti, J.]]
 [[Category: Kaur, P.]]
-[[Category: Singh, T.P.]]
+[[Category: Singh, T P.]]
 [[Category: Srinivasan, A.]]
 [[Category: 9AR]]
@@ Line 30: / Line 30: @@
 [[Category: structure]]
-''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Tue Nov 20 15:19:30 2007''
+''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 12:42:57 2008''