title: The binding mode of cladocoran A to the human group IIA phospholipase A(2).
abstract: The molecular basis for human group IIA phospholipase A(2)  inactivation by the marine natural product cladocoran A (CLD A) has been studied in order to elucidate its relevant anti-inflammatory properties. Indeed, secretory phospholipases A(2)  are well-known to be implicated in the pathogenesis of inflammation, such as rheumatoid arthritis, septic shock, psoriasis and asthma, thus the understanding of their inactivation mechanism could be useful for the development of new chemical classes of selective inhibitors. Our results, collected by a combination of biochemical approaches, advanced mass spectrometry and molecular modeling, suggest a competitive inhibition mechanism guided by a noncovalent molecular recognition event, and disclose the key role of the CLD A γ-hydroxybutenolide ring in the chelation of the catalytic calcium ion inside the enzyme active site. Moreover, CLD A is able to react selectively with Ser82, although this covalent event seems to play a secondary role in terms of enzyme inhibition.
authors.affiliation: Dipartimento di Scienze Farmaceutiche e Biomediche, Università degli Studi di Salerno, Via Ponte Don Melillo, 84084 Fisciano, Italy.
authors.forename: Maria Chiara
authors.initials: MC
authors.lastname: Monti
authors.forename: Maria Giovanna
authors.initials: MG
authors.lastname: Chini
authors.forename: Luigi
authors.initials: L
authors.lastname: Margarucci
authors.forename: Raffaele
authors.initials: R
authors.lastname: Riccio
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Bifulco
authors.forename: Agostino
authors.initials: A
authors.lastname: Casapullo
mesh_terms: D015107:4-Butyrolactone / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism; D000893:Anti-Inflammatory Agents / Q000737:chemistry / Q000378:metabolism; D001665:Binding Sites; D002118:Calcium / Q000737:chemistry; D020134:Catalytic Domain; D006801:Humans; D008958:Models, Molecular; D064801:Phospholipase A2 Inhibitors; D054467:Phospholipases A2 / Q000378:metabolism*; D011485:Protein Binding; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
chemical_list: D000893:Anti-Inflammatory Agents; D064801:Phospholipase A2 Inhibitors; C479318:cladocoran A; D054467:Phospholipases A2; D015107:4-Butyrolactone; D002118:Calcium