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Article ; Online: Structure-Based Optimization of Protease-Inhibitor Interactions to Enhance Specificity of Human Stefin-A against Falcipain-2 from the

Chakraborty, Subhoja / Biswas, Sampa

2023 Volume 62, Issue 5, Page(s) 1053–1069

Abstract: The emergence of resistance ... ...

Abstract	The emergence of resistance in
MeSH term(s)	Humans ; Plasmodium falciparum ; Protease Inhibitors/metabolism ; Cystatins/metabolism ; Cathepsins/metabolism ; Anti-Infective Agents ; Cysteine Proteinase Inhibitors/chemistry ; Antimalarials/chemistry ; Enzyme Inhibitors/metabolism
Chemical Substances	falcipain 2 (EC 3.4.22.-) ; Protease Inhibitors ; Cystatins ; Cathepsins (EC 3.4.-) ; Anti-Infective Agents ; Cysteine Proteinase Inhibitors ; Antimalarials ; Enzyme Inhibitors
Language	English
Publishing date	2023-02-10
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1108-3
ISSN	1520-4995 ; 0006-2960
ISSN (online)	1520-4995
ISSN	0006-2960
DOI	10.1021/acs.biochem.2c00585
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Article ; Online: Structure-guided protein engineering of human cathepsin L for efficient collagenolytic activity.

Choudhury, Debi / Biswas, Sampa

Protein engineering, design & selection : PEDS

2021 Volume 34

Abstract: Engineering precise substrate specificity of proteases advances the potential to use them in biotechnological and therapeutic applications. Collagen degradation, a physiological process mediated by collagenases, is an integral part of extracellular ... ...

Abstract	Engineering precise substrate specificity of proteases advances the potential to use them in biotechnological and therapeutic applications. Collagen degradation, a physiological process mediated by collagenases, is an integral part of extracellular matrix remodeling and when uncontrolled, implicated in different pathological conditions. Lysosomal cathepsin-K cleaves triple helical collagen fiber, whereas cathepsin-L cannot do so. In this study, we have imparted collagenolytic property to cathepsin-L, by systematically engineering proline-specificity and glycosaminoglycans (GAG)-binding surface in the protease. The proline-specific mutant shows high specificity for prolyl-peptidic substrate but is incapable of cleaving collagen. Engineering a GAG-binding surface on the proline-specific mutant enabled it to degrade type-I collagen in the presence of chondroitin-4-sulfate (C4-S). We also present the crystal structures of proline-specific (1.4 Å) and collagen-specific (1.8 Å) mutants. Finally docking studies with prolyl-peptidic substrate (Ala-Gly-Pro-Arg-Ala) at the active site and a C4-S molecule at the GAG-binding site enable us to identify key structural features responsible for collagenolytic activity of cysteine cathepsins.
MeSH term(s)	Cathepsin L ; Chondroitin Sulfates ; Collagenases/metabolism ; Glycosaminoglycans ; Humans ; Protein Engineering ; Substrate Specificity
Chemical Substances	Glycosaminoglycans ; Chondroitin Sulfates (9007-28-7) ; Cathepsin L (EC 3.4.22.15) ; Collagenases (EC 3.4.24.-)
Language	English
Publishing date	2021-04-07
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1466729-0
ISSN	1741-0134 ; 1741-0126
ISSN (online)	1741-0134
ISSN	1741-0126
DOI	10.1093/protein/gzab005
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Article: New insights of falcipain 2 structure from Plasmodium falciparum 3D7 strain

Chakraborty, Subhoja / Alam, Benazir / Biswas, Sampa

Biochemical and biophysical research communications. 2022 Jan. 29, v. 590

2022

Abstract: Malaria identifies as a tropical hallmark, conforming to the burgeoning notion of escalating drug resistance among virulent strains, with the burdensome Plasmodium falciparum under its wing. The cysteine protease Falcipain-2 (FP2) is released in the ... ...

Abstract	Malaria identifies as a tropical hallmark, conforming to the burgeoning notion of escalating drug resistance among virulent strains, with the burdensome Plasmodium falciparum under its wing. The cysteine protease Falcipain-2 (FP2) is released in the parasite's food vacuole in the trophozoite stage and contributes to disease progression through its hemoglobinase activity. In the present study, we have determined the crystal structure of FP2 from a drug resistant P. falciparum 3D7 strain. FP2-3D7 sequence has detected four amino acid variants, R12K, E14 N, P100T and G102D, in the mature domain of the protease, when compared with other reported structures. FP2-3D7 protease has been crystallized in the presence of two inhibitors E−64 and Iodoacetamide, which diffracted up to 3.5 Å and 3.4 Å respectively. Structural analyses of the mature domain helped unveil two solvent-exposed pockets with bound ligands where one is structurally homologous to the allosteric binding site of human Cathepsin-K and thus, could be exploited for designing allosteric modifiers of FP2. The structure has also revealed (poly)ethylene glycol molecules along the catalytic cleft, providing interesting insights for exploring FP2 as a chemotherapeutic target and for PEGylation in drug delivery. The side-chains of P2 and P3 residues of E−64 also adopt different rotamer conformations, compared with previously reported structure, emphasizing strain-specific multiple binding-modes of active-site targeted inhibitors. Docking studies, along with normal mode analyses, highlight the mode of hemoglobin binding and the active/inactive switch in hemoglobinase activity, conjecturing the formation of a stable dimeric state with a symmetry related copy in crystal packing.
Keywords	Plasmodium falciparum ; active sites ; amino acids ; cathepsin K ; chemical bonding ; crystal structure ; disease progression ; drug resistance ; drug therapy ; drugs ; ethylene glycol ; hemoglobin ; humans ; ligands ; malaria ; parasites ; research ; vacuoles ; virulence
Language	English
Dates of publication	2022-0129
Size	p. 145-151.
Publishing place	Elsevier Inc.
Document type	Article
ZDB-ID	205723-2
ISSN	0006-291X ; 0006-291X
ISSN (online)	0006-291X
ISSN	0006-291X
DOI	10.1016/j.bbrc.2021.12.080
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Article ; Online: Inhibition of Plasmodium falciparum cysteine protease falcipain-2 by a human cross-class inhibitor serpinB3: A mechanistic insight.

Alam, Benazir / Biswas, Sampa

Biochimica et biophysica acta. Proteins and proteomics

2019 Volume 1867, Issue 9, Page(s) 854–865

Abstract: Falcipain-2(FP2), a cysteine protease from Plasmodium falciparum, cleaves host erythrocyte hemoglobin and specific membrane skeleton components during the parasite life cycle. Therefore its inhibition has been considered as an attractive approach to ... ...

Abstract	Falcipain-2(FP2), a cysteine protease from Plasmodium falciparum, cleaves host erythrocyte hemoglobin and specific membrane skeleton components during the parasite life cycle. Therefore its inhibition has been considered as an attractive approach to combat the disease. SerpinB3 (SPB3) belongs to the ovalbumin-serpin family and is a potent cross-class inhibitor of cysteine cathepsins L, K, S and papain. This study explored the possibility of inhibition of FP2 by SPB3. It turned out that general proteolytic activities as well as specific hemoglobinolytic activity of FP2 have been inhibited by SPB3. Furthermore, studies have been designed to investigate and characterize the mechanism of inhibition in comparison with proteases Cathepsin L (CTSL) and papain. The Ki value of inhibition for FP2, measured against its specific substrate (VLK-pNA), is 338.11 nM and stoichiometry (I/E ratio) of inhibition is 1. These values are comparable to CTSL and papain. Analytical gel filtration profile and CD spectroscopy data confirm FP2-SPB3 complex formation. Our studies revealed that interaction of SPB3 with FP2 is non-covalent type like that of CTSL and papain but unlike other serine protease-inhibiting serpins. An in-silico docking and simulation study have been performed with FP2 as well as CTSL and results suggest different binding mode for FP2 and CTSL, though both the complexes are stable with significant contribution from electrostatic energy of interaction. We further showed a disease state mutant SPB3-Gly351Ala performed better anti-protease activity against FP2. This study, for the first time, has shown a serpin family inhibitor from human could efficiently inhibit activity of FP2.
MeSH term(s)	Antigens, Neoplasm/chemistry ; Antigens, Neoplasm/genetics ; Antigens, Neoplasm/metabolism ; Cathepsin L/antagonists & inhibitors ; Cathepsin L/chemistry ; Cathepsin L/genetics ; Cathepsin L/metabolism ; Cysteine Endopeptidases/chemistry ; Cysteine Endopeptidases/genetics ; Cysteine Endopeptidases/metabolism ; Humans ; Molecular Docking Simulation ; Papain/antagonists & inhibitors ; Papain/chemistry ; Papain/genetics ; Papain/metabolism ; Plasmodium falciparum/enzymology ; Plasmodium falciparum/genetics ; Serpins/chemistry ; Serpins/genetics ; Serpins/metabolism
Chemical Substances	Antigens, Neoplasm ; Serpins ; squamous cell carcinoma-related antigen ; Cysteine Endopeptidases (EC 3.4.22.-) ; falcipain 2 (EC 3.4.22.-) ; CTSL protein, human (EC 3.4.22.15) ; Cathepsin L (EC 3.4.22.15) ; Papain (EC 3.4.22.2)
Language	English
Publishing date	2019-06-24
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2918798-9
ISSN	1878-1454 ; 1570-9639
ISSN (online)	1878-1454
ISSN	1570-9639
DOI	10.1016/j.bbapap.2019.06.012
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Article ; Online: New insights of falcipain 2 structure from Plasmodium falciparum 3D7 strain.

Chakraborty, Subhoja / Alam, Benazir / Biswas, Sampa

Biochemical and biophysical research communications

2021 Volume 590, Page(s) 145–151

Abstract	Malaria identifies as a tropical hallmark, conforming to the burgeoning notion of escalating drug resistance among virulent strains, with the burdensome Plasmodium falciparum under its wing. The cysteine protease Falcipain-2 (FP2) is released in the parasite's food vacuole in the trophozoite stage and contributes to disease progression through its hemoglobinase activity. In the present study, we have determined the crystal structure of FP2 from a drug resistant P. falciparum 3D7 strain. FP2-3D7 sequence has detected four amino acid variants, R12K, E14 N, P100T and G102D, in the mature domain of the protease, when compared with other reported structures. FP2-3D7 protease has been crystallized in the presence of two inhibitors E-64 and Iodoacetamide, which diffracted up to 3.5 Å and 3.4 Å respectively. Structural analyses of the mature domain helped unveil two solvent-exposed pockets with bound ligands where one is structurally homologous to the allosteric binding site of human Cathepsin-K and thus, could be exploited for designing allosteric modifiers of FP2. The structure has also revealed (poly)ethylene glycol molecules along the catalytic cleft, providing interesting insights for exploring FP2 as a chemotherapeutic target and for PEGylation in drug delivery. The side-chains of P2 and P3 residues of E-64 also adopt different rotamer conformations, compared with previously reported structure, emphasizing strain-specific multiple binding-modes of active-site targeted inhibitors. Docking studies, along with normal mode analyses, highlight the mode of hemoglobin binding and the active/inactive switch in hemoglobinase activity, conjecturing the formation of a stable dimeric state with a symmetry related copy in crystal packing.
MeSH term(s)	Allosteric Site ; Amino Acids/genetics ; Catalytic Domain ; Cystatins ; Cysteine Endopeptidases/chemistry ; Cysteine Endopeptidases/metabolism ; Ethylenes/chemistry ; Hemoglobins/metabolism ; Ligands ; Models, Molecular ; Plasmodium falciparum/enzymology ; Polyethylene Glycols/chemistry ; Polymorphism, Single Nucleotide/genetics ; Protein Domains ; Proteolysis ; Solvents ; Substrate Specificity
Chemical Substances	Amino Acids ; Cystatins ; Ethylenes ; Hemoglobins ; Ligands ; Solvents ; Polyethylene Glycols (3WJQ0SDW1A) ; ethylene (91GW059KN7) ; Cysteine Endopeptidases (EC 3.4.22.-) ; falcipain 2 (EC 3.4.22.-)
Language	English
Publishing date	2021-12-23
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	205723-2
ISSN	1090-2104 ; 0006-291X ; 0006-291X
ISSN (online)	1090-2104 ; 0006-291X
ISSN	0006-291X
DOI	10.1016/j.bbrc.2021.12.080
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Article: Inhibition of Plasmodium falciparum cysteine protease falcipain-2 by a human cross-class inhibitor serpinB3: A mechanistic insight

Alam, Benazir / Biswas, Sampa

Biochimica et biophysica acta. 2019 Sept., v. 1867, no. 9

2019

Abstract	Falcipain-2(FP2), a cysteine protease from Plasmodium falciparum, cleaves host erythrocyte hemoglobin and specific membrane skeleton components during the parasite life cycle. Therefore its inhibition has been considered as an attractive approach to combat the disease. SerpinB3 (SPB3) belongs to the ovalbumin-serpin family and is a potent cross-class inhibitor of cysteine cathepsins L, K, S and papain. This study explored the possibility of inhibition of FP2 by SPB3. It turned out that general proteolytic activities as well as specific hemoglobinolytic activity of FP2 have been inhibited by SPB3. Furthermore, studies have been designed to investigate and characterize the mechanism of inhibition in comparison with proteases Cathepsin L (CTSL) and papain. The Ki value of inhibition for FP2, measured against its specific substrate (VLK-pNA), is 338.11 nM and stoichiometry (I/E ratio) of inhibition is 1. These values are comparable to CTSL and papain. Analytical gel filtration profile and CD spectroscopy data confirm FP2-SPB3 complex formation. Our studies revealed that interaction of SPB3 with FP2 is non-covalent type like that of CTSL and papain but unlike other serine protease-inhibiting serpins. An in-silico docking and simulation study have been performed with FP2 as well as CTSL and results suggest different binding mode for FP2 and CTSL, though both the complexes are stable with significant contribution from electrostatic energy of interaction. We further showed a disease state mutant SPB3-Gly351Ala performed better anti-protease activity against FP2. This study, for the first time, has shown a serpin family inhibitor from human could efficiently inhibit activity of FP2.
Keywords	cathepsin L ; cell membranes ; circular dichroism spectroscopy ; computer simulation ; cysteine ; electrostatic interactions ; energy ; enzyme activity ; erythrocytes ; gel chromatography ; hemoglobin ; humans ; mutants ; papain ; parasites ; Plasmodium falciparum ; proteolysis ; serpins ; stoichiometry
Language	English
Dates of publication	2019-09
Size	p. 854-865.
Publishing place	Elsevier B.V.
Document type	Article
ZDB-ID	2918798-9
ISSN	1878-1454 ; 1570-9639
ISSN (online)	1878-1454
ISSN	1570-9639
DOI	10.1016/j.bbapap.2019.06.012
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Article ; Online: Highly Conserved Arg Residue of ERFNIN Motif of Pro-Domain is Important for pH-Induced Zymogen Activation Process in Cysteine Cathepsins K and L.

Aich, Pulakesh / Biswas, Sampa

Cell biochemistry and biophysics

2018 Volume 76, Issue 1-2, Page(s) 219–229

Abstract: Pro-domain of a cysteine cathepsin contains a highly conserved ... ...

Abstract	Pro-domain of a cysteine cathepsin contains a highly conserved Ex
MeSH term(s)	Amino Acid Motifs ; Amino Acid Sequence ; Arginine/chemistry ; Arginine/metabolism ; Cathepsin K/chemistry ; Cathepsin K/genetics ; Cathepsin K/metabolism ; Cathepsin L/chemistry ; Cathepsin L/genetics ; Cathepsin L/metabolism ; Circular Dichroism ; Enzyme Precursors/chemistry ; Enzyme Precursors/metabolism ; Humans ; Hydrogen-Ion Concentration ; Kinetics ; Models, Molecular ; Mutagenesis, Site-Directed ; Protein Structure, Tertiary ; Spectrometry, Fluorescence ; Substrate Specificity
Chemical Substances	Enzyme Precursors ; Arginine (94ZLA3W45F) ; Cathepsin L (EC 3.4.22.15) ; Cathepsin K (EC 3.4.22.38)
Language	English
Publishing date	2018-06
Publishing country	United States
Document type	Journal Article
ZDB-ID	1357904-6
ISSN	1559-0283 ; 1085-9195
ISSN (online)	1559-0283
ISSN	1085-9195
DOI	10.1007/s12013-017-0838-x
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Article ; Online: Exploring protein-protein intermolecular recognition between meprin-α and endogenous protease regulator cystatinC coupled with pharmacophore elucidation.

Chaudhuri, Ankur / Biswas, Sampa / Chakraborty, Sibani

Journal of biomolecular structure & dynamics

2018 Volume 37, Issue 2, Page(s) 440–453

Abstract: Meprins are a group of zinc metalloproteases of the astacin family which play a pivotal role in several physiological and pathologocal diseases. The inhibition of the meprins by various inhibitors, macromolecular and small molecules, is crucial in the ... ...

Abstract	Meprins are a group of zinc metalloproteases of the astacin family which play a pivotal role in several physiological and pathologocal diseases. The inhibition of the meprins by various inhibitors, macromolecular and small molecules, is crucial in the control of several diseases. Human cystatinC, an amyloidogenic protein, is reported to be an endogenous inhibitor of meprin-α. In this computational study, we elucidate a rational model for meprinα-cystatinC complex using protein-protein docking. The complex model as well as the unbound form was evaluated by molecular dynamics simulation. A simulation study revealed higher stability of the complex owing to the presence of several interactions. Virtual alanine mutagenesis helps in identifying the hotspots on both proteins. Based on the frequency of occurrence of hotspot amino acids, it was possible to enumerate the important amino acids primarily responsible for protein stability present at the amino-terminal end of cystatin. Finally, pharmacophore elucidation carried out based on the information obtained from a series of small molecular inhibitors against meprin-α can be utilized in future for rational drug design and therapy.
MeSH term(s)	Drug Discovery ; Enzyme Stability ; Humans ; Hydrogen Bonding ; Hydrophobic and Hydrophilic Interactions ; Ligands ; Metalloendopeptidases/chemistry ; Metalloendopeptidases/metabolism ; Molecular Docking Simulation ; Molecular Dynamics Simulation ; Protein Binding ; Protein Interaction Domains and Motifs ; Protein Subunits ; Reproducibility of Results ; Structure-Activity Relationship
Chemical Substances	Ligands ; Protein Subunits ; Metalloendopeptidases (EC 3.4.24.-) ; meprin A (EC 3.4.24.18) ; astacin (EC 3.4.24.21)
Language	English
Publishing date	2018-02-07
Publishing country	England
Document type	Journal Article
ZDB-ID	49157-3
ISSN	1538-0254 ; 0739-1102
ISSN (online)	1538-0254
ISSN	0739-1102
DOI	10.1080/07391102.2018.1429311
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Article ; Online: Not all pycnodysostosis-related mutants of human cathepsin K are inactive - crystal structure and biochemical studies of an active mutant I249T.

Roy, Sumana / Das Chakraborty, Sudeshna / Biswas, Sampa

The FEBS journal

2018 Volume 285, Issue 22, Page(s) 4265–4280

Abstract: Human cathepsin K (CTSK) is a collagenolytic lysosomal cysteine protease that plays an important role in bone turnover. Mutation in CTSK gene is associated with loss of collagenolytic activity of CTSK leading to an autosomal recessive bone disorder ... ...

Abstract	Human cathepsin K (CTSK) is a collagenolytic lysosomal cysteine protease that plays an important role in bone turnover. Mutation in CTSK gene is associated with loss of collagenolytic activity of CTSK leading to an autosomal recessive bone disorder called pycnodysostosis. Although a number of pycnodysostotic missense mutations have been reported, underlying mechanism of the disease is not clear. In this study, we investigated in vitro six recombinant pycnodysostosis-related mutants of human CTSK (G79E, I249T, G243E, G303E, G319C and Q187P). While all the mutants, like wild-type, show similar high levels of expression in Escherichia coli, four of them (G79E, G303E, G319C and Q187P) are inactive, unstable and spontaneously degrade during purification process. In contrast, proteolytic/collagenolytic activity, zymogen activation kinetics and stability of G243E and I249T mutants are nominally affected. Crystal structure of I249T at 1.92 Å resolution shows that the mutation in R-domain causes conformational changes of a surface loop in the L-domain although the catalytic cleft remains unaltered. Molecular simulation, normal mode analysis and fluorescence lifetime measurement eliminated the possibility that the change in L-domain surface loop orientation is a crystallization artefact. CD-based thermal melting profile indicates that stability of I249T is significantly higher than wild-type. Our studies first time reports that pycnodysostosis-related mutations do not always lead to complete loss of general proteolytic activity or specific collagenolytic activity of CTSK. The first crystal structure of a pycnodysostotic mutant (I249T) provides critical information that may pave new avenues towards understanding the disease at molecular level. DATABASE: The atomic co-ordinates and structure factors for I249T mutant of human CTSK (codes 5Z5O) have been deposited in the Protein Data Bank (http://wwpdb.org/).
MeSH term(s)	Amino Acid Sequence ; Catalysis ; Cathepsin K/chemistry ; Cathepsin K/genetics ; Cathepsin K/metabolism ; Crystallography, X-Ray ; DNA Mutational Analysis ; Humans ; Models, Molecular ; Mutation ; Protein Conformation ; Pycnodysostosis/genetics ; Sequence Homology
Chemical Substances	CTSK protein, human (EC 3.4.22.38) ; Cathepsin K (EC 3.4.22.38)
Language	English
Publishing date	2018-09-26
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2173655-8
ISSN	1742-4658 ; 1742-464X
ISSN (online)	1742-4658
ISSN	1742-464X
DOI	10.1111/febs.14655
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Article: Characterizations of SARS-CoV-2 mutational profile, spike protein stability and viral transmission

Laha, Sayantan / Chakraborty, Joyeeta / Das, Shantanab / Manna, Soumen Kanti / Biswas, Sampa / Chatterjee, Raghunath

Infection, genetics, and evolution. 2020 Nov., v. 85

2020

Abstract: The recent pandemic of SARS-CoV-2 infection has affected more than 3.0 million people worldwide with more than 200 thousand reported deaths. The SARS-CoV-2 genome has the capability of gaining rapid mutations as the virus spreads. Whole-genome sequencing ...

Abstract	The recent pandemic of SARS-CoV-2 infection has affected more than 3.0 million people worldwide with more than 200 thousand reported deaths. The SARS-CoV-2 genome has the capability of gaining rapid mutations as the virus spreads. Whole-genome sequencing data offers a wide range of opportunities to study mutation dynamics. The advantage of an increasing amount of whole-genome sequence data of SARS-CoV-2 intrigued us to explore the mutation profile across the genome, to check the genome diversity, and to investigate the implications of those mutations in protein stability and viral transmission. We have identified frequently mutated residues by aligning ~660 SARS-CoV-2 genomes and validated in 10,000 datasets available in GISAID Nextstrain. We further evaluated the potential of these frequently mutated residues in protein structure stability of spike glycoprotein and their possible functional consequences in other proteins. Among the 11 genes, surface glycoprotein, nucleocapsid, ORF1ab, and ORF8 showed frequent mutations, while envelop, membrane, ORF6, ORF7a and ORF7b showed conservation in terms of amino acid substitutions. Combined analysis with the frequently mutated residues identified 20 viral variants, among which 12 specific combinations comprised more than 97% of the isolates considered for the analysis. Some of the mutations across different proteins showed co-occurrences, suggesting their structural and/or functional interaction among different SARS-COV-2 proteins, and their involvement in adaptability and viral transmission. Analysis of protein structure stability of surface glycoprotein mutants indicated the viability of specific variants and are more prone to be temporally and spatially distributed across the globe. A similar empirical analysis of other proteins indicated the existence of important functional implications of several variants. Identification of frequently mutated variants among COVID-19 patients might be useful for better clinical management, contact tracing, and containment of the disease.
Keywords	COVID-19 infection ; Severe acute respiratory syndrome coronavirus 2 ; amino acids ; data collection ; empirical research ; evolution ; glycoproteins ; infection ; nucleocapsid ; pandemic ; people ; protein structure ; viability ; virus transmission ; viruses
Language	English
Dates of publication	2020-11
Publishing place	Elsevier B.V.
Document type	Article
Note	NAL-AP-2-clean
ZDB-ID	2037068-4
ISSN	1567-1348
ISSN	1567-1348
DOI	10.1016/j.meegid.2020.104445
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