%0 Journal Article %T Crystal Structure of Isoform CBd of the Basic Phospholipase A2 Subunit of Crotoxin: Description of the Structural Framework of CB for Interaction with Protein Targets %+ Récepteurs Canaux - Channel Receptors %+ Nicolaus Copernicus University [Toruń] %+ Sanofi-Aventis R&D %+ Cristallographie (Plateforme) - Crystallography (Platform) %A Nemecz, Dorota %A Ostrowski, Maciej %A Ravatin, Marc %A Saul, Frederick %A Faure, Grazyna %Z M.O. and D.N. received research fellowships within project “Enhancing Educational Potential of Nicolaus Copernicus University in the Disciplines of Mathematical and Natural Sciences” (project no. POKL.04.01.01-00-081/10) %< avec comité de lecture %@ 1420-3049 %J Molecules %I MDPI %S Special Issue Toxins of Natural Origin: From Venom of Animals or Plants %V 25 %N 22 %P 5290 %8 2020-11-13 %D 2020 %R 10.3390/molecules25225290 %M 33202772 %K phospholipase A 2 isoforms crystal structure protein-protein interaction anticoagulant binding site CFTR binding interface %K phospholipase A 2 isoforms %K crystal structure %K protein-protein interaction %K anticoagulant binding site %K CFTR binding interface %Z Life Sciences [q-bio] %Z Chemical SciencesJournal articles %X Crotoxin, from the venom of the South American rattlesnake Crotalus durissus terrificus, is a potent heterodimeric presynaptic β-neurotoxin that exists in individual snake venom as a mixture of isoforms of a basic phospholipase A2 (PLA2) subunit (CBa2, CBb, CBc, and CBd) and acidic subunit (CA1–4). Specific natural mutations in CB isoforms are implicated in functional differences between crotoxin isoforms. The three-dimensional structure of two individual CB isoforms (CBa2, CBc), and one isoform in a crotoxin (CA2CBb) complex, have been previously reported. This study concerns CBd, which by interaction with various protein targets exhibits many physiological or pharmacological functions. It binds with high affinity to presynaptic receptors showing neurotoxicity, but also interacts with human coagulation factor Xa (hFXa), exhibiting anticoagulant effect, and acts as a positive allosteric modulator and corrector of mutated chloride channel, cystic fibrosis transmembrane conductance regulator (CFTR), implicated in cystic fibrosis. Thus, CBd represents a novel family of agents that have potential in identifying new drug leads related to anticoagulant and anti-cystic fibrosis function. We determined here the X-ray structure of CBd and compare it with the three other natural isoforms of CB. The structural role of specific amino acid variations between CB isoforms are analyzed and the structural framework of CB for interaction with protein targets is described. %G English %Z We thank Ahmed Haouz and Patrick Weber of the crystallography platform at the Institut Pasteur for assistance and access to automated crystallization screening facilities. We acknowledge SOLEIL for provision of synchrotron radiation facilities and we would like to thank the personnel of beamlines Proxima-1 and Proxima-2 for assistance. We are grateful to Ákos Nemecz for critical reading of the manuscript and for helpful suggestions. %2 https://pasteur.hal.science/pasteur-04102938/document %2 https://pasteur.hal.science/pasteur-04102938/file/Nemecz%20molecules-25-05290.pdf %L pasteur-04102938 %U https://pasteur.hal.science/pasteur-04102938 %~ PASTEUR %~ CNRS %~ UNIV-PARIS %~ UNIVERSITE-PARIS %~ CHAN-RECEPTORS %~ PASTEUR_UMR3571