1FV0

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

Summary for 1FV0

• Entry DOI: 10.2210/pdb1fv0/pdb
• Related: 1CL5 1FE7
• Descriptor: PHOSPHOLIPASE A2, SULFATE ION, ACETATE ION, ... (7 entities in total)
• Functional Keywords: phospholipase a2, daboia russelli pulchella, neurotoxic, edema, toxin
• Biological source: Daboia russellii pulchella
• Cellular location: Secreted : P59071
• Total number of polymer chains: 2
• Total formula weight: 28420.50

Authors

Chandra, V.,Jasti, J.,Kaur, P.,Srinivasan, A.,Betzel, C.,Singh, T.P. (deposition date: 2000-09-18, release date: 2002-08-28, Last modification date: 2024-11-20)

Primary citation

Chandra, V.,Jasti, J.,Kaur, P.,Srinivasan, A.,Betzel, C.,Singh, T.P.
Structural Basis of Phospholipase A2 Inhibition for the Synthesis of Prostaglandins by the Plant Alkaloid Aristolochic Acid from a 1.7 A Crystal Structure
Biochemistry, 41:10914-10919, 2002

PubMed Abstract: 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).

PubMed: 12206661
DOI: 10.1021/bi0258593

Experimental method

X-RAY DIFFRACTION (1.7 Å)