Identification of accelerated evolution in the metalloproteinase domain of snake venom metalloproteinase sequences (SVMPs) through comparative analysis
Abstract:Computational protein sequence analysis is one of the most important tools used for understanding the evolution of closely related proteins sequences including snake venom metalloproteinase sequences (SVMPs) which give valuable information regarding genetic variations. The fundamental objective of the present study is to screen the evolution distributed in metalloproteinase domain regions of protein sequences among different SVMPs in snake species which are involved in a range of pathological disorders such as… Show more
“…SVMP structures have a typical topology, consisting of six α-helices and five stranded β-sheets in the M domain where the zinc ion is localized. Besides, sequence comparison between the M domains of SVMPs reveals quite high identity values of around 66% . This chemical and stereochemical match, particularly at the active site region, allows us to hypothesize that many of the members of this family of enzymes share a common catalytic mechanism.…”
Section: Introductionmentioning
confidence: 84%
“…Besides, sequence comparison between the M domains of SVMPs reveals quite high identity values of around 66%. 65 This chemical and stereochemical match, particularly at the active site region, allows us to hypothesize that many of the members of this family of enzymes share a common catalytic mechanism. Therefore, our results concerning the intricacies of the RVV-X mechanism might be extrapolated to many other members of this vast family.…”
Snake venom metalloproteinases
(SVMPs) are important
drug targets
against snakebite envenoming, the neglected tropical disease with
the highest mortality worldwide. Here, we focus on Russell’s
viper (Daboia russelii), one of the
“big four” snakes of the Indian subcontinent that, together,
are responsible for ca. 50,000 fatalities annually. The “Russell’s
viper venom factor X activator” (RVV-X), a highly toxic metalloproteinase,
activates the blood coagulation factor X (FX), leading to the prey’s
abnormal blood clotting and death. Given its tremendous public health
impact, the WHO recognized an urgent need to develop efficient, heat-stable,
and affordable-for-all small-molecule inhibitors, for which a deep
understanding of the mechanisms of action of snake’s principal
toxins is fundamental. In this study, we determine the catalytic mechanism
of RVV-X by using a density functional theory/molecular mechanics
(DFT:MM) methodology to calculate its free energy profile. The results
showed that the catalytic process takes place via two steps. The first
step involves a nucleophilic attack by an in situ generated hydroxide
ion on the substrate carbonyl, yielding an activation barrier of 17.7
kcal·mol–1, while the second step corresponds
to protonation of the peptide nitrogen and peptide bond cleavage with
an energy barrier of 23.1 kcal·mol–1. Our study
shows a unique role played by Zn2+ in catalysis by lowering
the pK
a of the Zn2+-bound water
molecule, enough to permit the swift formation of the hydroxide nucleophile
through barrierless deprotonation by the formally much less basic
Glu140. Without the Zn2+ cofactor, this step would be rate-limiting.
“…SVMP structures have a typical topology, consisting of six α-helices and five stranded β-sheets in the M domain where the zinc ion is localized. Besides, sequence comparison between the M domains of SVMPs reveals quite high identity values of around 66% . This chemical and stereochemical match, particularly at the active site region, allows us to hypothesize that many of the members of this family of enzymes share a common catalytic mechanism.…”
Section: Introductionmentioning
confidence: 84%
“…Besides, sequence comparison between the M domains of SVMPs reveals quite high identity values of around 66%. 65 This chemical and stereochemical match, particularly at the active site region, allows us to hypothesize that many of the members of this family of enzymes share a common catalytic mechanism. Therefore, our results concerning the intricacies of the RVV-X mechanism might be extrapolated to many other members of this vast family.…”
Snake venom metalloproteinases
(SVMPs) are important
drug targets
against snakebite envenoming, the neglected tropical disease with
the highest mortality worldwide. Here, we focus on Russell’s
viper (Daboia russelii), one of the
“big four” snakes of the Indian subcontinent that, together,
are responsible for ca. 50,000 fatalities annually. The “Russell’s
viper venom factor X activator” (RVV-X), a highly toxic metalloproteinase,
activates the blood coagulation factor X (FX), leading to the prey’s
abnormal blood clotting and death. Given its tremendous public health
impact, the WHO recognized an urgent need to develop efficient, heat-stable,
and affordable-for-all small-molecule inhibitors, for which a deep
understanding of the mechanisms of action of snake’s principal
toxins is fundamental. In this study, we determine the catalytic mechanism
of RVV-X by using a density functional theory/molecular mechanics
(DFT:MM) methodology to calculate its free energy profile. The results
showed that the catalytic process takes place via two steps. The first
step involves a nucleophilic attack by an in situ generated hydroxide
ion on the substrate carbonyl, yielding an activation barrier of 17.7
kcal·mol–1, while the second step corresponds
to protonation of the peptide nitrogen and peptide bond cleavage with
an energy barrier of 23.1 kcal·mol–1. Our study
shows a unique role played by Zn2+ in catalysis by lowering
the pK
a of the Zn2+-bound water
molecule, enough to permit the swift formation of the hydroxide nucleophile
through barrierless deprotonation by the formally much less basic
Glu140. Without the Zn2+ cofactor, this step would be rate-limiting.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.