Crystal structure of Jararacussin‐I: The highly negatively charged catalytic interface contributes to macromolecular selectivity in snake venom thrombin‐like enzymes

Abstract

Snake venom serine proteinases (SVSPs) are hemostatically active toxins that perturb the maintenance and regulation of both the blood coagulation cascade and fibrinolytic feedback system at specific points, and hence, are widely used as tools in pharmacological and clinical diagnosis. The crystal structure of a thrombin-like enzyme (TLE) from Bothrops jararacussu venom (Jararacussin-I) was determined at 2.48 Å resolution. This is the first crystal structure of a TLE and allows structural comparisons with both the Agkistrodon contortrix contortrix Protein C Activator and the Trimeresurus stejnegeri plasminogen activator. Despite the highly conserved overall fold, significant differences in the amino acid compositions and three-dimensional conformations of the loops surrounding the active site significantly alter the molecular topography and charge distribution profile of the catalytic interface. In contrast to other SVSPs, the catalytic interface of Jararacussin-I is highly negatively charged, which contributes to its unique macromolecular selectivity.

Constructing comprehensive venom proteome reference maps for integrative venomics

“…Although the occurrence of some nominal proteins in different RP-HPLC peaks and/or SDS-PAGE bands indicated chromatographic carryover and/or the existence of iso/proteoforms (e.g., SVSPs 5 and 8; FIGURES 1 & 2), other serine proteinase molecules, including SVSPs 11 (J3S832), 3, 2 and 6, were associated with unique fractions and protein bands. The isotope-averaged ESI-MS-determined molecular mass (M ave ) of native SVSP-11 (25353.2 Da) eluted in fraction 22 (FIGURES 1 & 2) was in perfect concordance with that calculated for its transcriptome-derived sequence with a T/I substitution at position 131 (tryptic peptide m/z 627.8 (4+) 130 EIYPDVPHCADI-NILDHAVCR 149 , SUPPLEMENTARY TABLE S1), indicating that this serine proteinase did not include post-translational modifications other than the canonical 6 intrachain disulfide bonds [56]. On the other hand, the M ave of SVSP-5 purified in the same fraction (25328.9 Da) was 16 Da higher than computed from its mRNA-derived protein sequence (F8S116).…”

Preliminary assessment of Hedychium coronarium essential oil on fibrinogenolytic and coagulant activity induced by Bothrops and Lachesis snake venoms

“…These results suggest that the compounds present in the oils may interact with specific non-fibrinogenolytic proteases involved in the coagulation disorders promoted by snake envenomations, thus ruling out a number of metalloproteases described in the literature, especially those isolated from the venoms of B. atrox (batroxase, BaTX-I botroxostatine and atroxlysin-I) and B. moojeni (BMMP-III and BthMP) [ 30 , 31 , 33 , 34 , 40 , 41 ] and highlighting the serineproteases mainly responsible for such coagulation disorders [ 35 , 36 , 41 - 45 ].…”

Envenomation by Trimeresurus stejnegeri stejnegeri: clinical manifestations, treatment and associated factors for wound necrosis

“…This degradation leads to the disruption of microvessel networks, edema, and hemorrhage [ 35 ]. SVSPs are hemostatically active toxins perturbing the maintenance and regulation of both the blood coagulation cascade and the fibrinolytic feedback system at specific points [ 37 ]. PLA 2 s have evolved into extremely potent toxins, displaying myotoxic, anticoagulant, and edema-inducing activities [ 17 , 38 ].…”