The Structure of Chagasin in Complex with a Cysteine Protease Clarifies the Binding Mode and Evolution of an Inhibitor Family

Wang, Stephanie X.; Pandey, Kailash C.; Scharfstein, Júlio; Whisstock, James C.; Huang, Rick; Jacobelli, Jordan; Fletterick, Robert J.; Rosenthal, Philip J.; Abrahamson, Magnus; Brinen, Linda S.; Rossi, Andrea; Šali, Andrej; McKerrow, James H.

doi:10.1016/j.str.2007.03.012

Cited by 72 publications

(98 citation statements)

References 32 publications

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“…They do not directly interact with the active-site residues. Instead, they occlude the active-site cysteine residue and prevent the approach of substrates (Stubbs et al , 1990 ;Turk et al , 1997Turk et al , , 2012Gunčar et al, 1999 ;Wang et al , 2007 ).…”

Section: Inhibition Of the C1 Family Cysteine Proteasesmentioning

confidence: 99%

“…In addition to the mycocypins, the mode of inhibitor binding to the C1 protease has been described for the cystatin (I25) (Stubbs et al , 1990 ) and thyropin (I31) families (Gunčar et al, 1999 ) as well as for chagasin (I42) (Wang et al , 2007 ;Redzynia et al , 2008 ). The inhibitors from these families have completely different folds but still use different loops to occlude the active-site residues.…”

Section: Inhibition Of the C1 Family Cysteine Proteasesmentioning

confidence: 99%

“…The inhibitors from these families have completely different folds but still use different loops to occlude the active-site residues. In contrast to two loops in clitocypins, proteins such as cystatins, thyropins, and chagasin provide three loops, which fi ll the active-site cleft (Stubbs et al , 1990 ;Gunč ar et al, 1999 ;Wang et al , 2007 ;Redzynia et al , 2008 ).…”

Section: Inhibition Of the C1 Family Cysteine Proteasesmentioning

confidence: 99%

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β-Trefoil inhibitors – from the work of Kunitz onward

Renko

Sabotič²,

Turk³

2012

Biological Chemistry

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Protein protease inhibitors are the tools of nature in controlling proteolytic enzymes. They come in different shapes and sizes. The β -trefoil protease inhibitors that come from plants, fi rst discovered by Kunitz, were later complemented with representatives from higher fungi. They inhibit serine (families S1 and S8) and cysteine proteases (families C1 and C13) as well as other hydrolases. Their versatility is the result of the plasticity of the loops coming out of the stable β -trefoil scaffold. For this reason, they display several different mechanisms of inhibition involving different positions of the loops and their combinations. Natural diversity, as well as the initial successes in de novo protein engineering, makes the β -trefoil proteins a promising starting point for the generation of strong, specifi c, multitarget inhibitors capable of inhibiting multiple types of hydrolytic enzymes and simultaneously interacting with different protein, carbohydrate, or DNA molecules. This pool of knowledge opens up new possibilities for the exploration of their naturally occurring as well as modifi ed properties for applications in many fi elds of medicine, biotechnology, and agriculture.

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Section: Inhibition Of the C1 Family Cysteine Proteasesmentioning

confidence: 99%

Section: Inhibition Of the C1 Family Cysteine Proteasesmentioning

confidence: 99%

Section: Inhibition Of the C1 Family Cysteine Proteasesmentioning

confidence: 99%

See 1 more Smart Citation

β-Trefoil inhibitors – from the work of Kunitz onward

Renko

Sabotič²,

Turk³

2012

Biological Chemistry

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“…The inhibitory constant (Ki) of cystatin for falcipain-2 and falcipain-3 are 6.5 and 100 nM, respectively (Wang et al 2007). It is interesting that cystatin is more potent inhibitor of falcipain-2 than falcipain-3, which suggests that cystatin regulate both the falcipains with different rate.…”

Section: Inhibition By Macromoleculesmentioning

confidence: 99%

“…The protease binding loops (BC, DE, and FG) in chagasin form a well-aligned wedge that fills the active site groove of falcipain-2 to obstruct substrate binding (Fig. 8 b) (Wang et al 2007). The BC loop is one of the three signature motifs that contribute mainly in inhibiting the cysteine protease.…”

Section: Inhibition By Macromoleculesmentioning

confidence: 99%

Centenary celebrations article

Pandey

2011

J Parasit Dis

Self Cite

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There is an urgent need for new drugs against malaria, which takes millions of lives annually. Cysteine proteases are potential new drug targets, especially when current drugs are showing resistance. Falcipains and vivapains are well characterized cysteine proteases of P. falciparum and P. vivax, respectively. Studies with cysteine protease inhibitors and manipulating cysteine proteases specific genes have suggested their roles in hemoglobin hydrolysis. In P. falciparum, falcipain-2 and falcipain-3 are major hemoglobinases that hydrolyze host erythrocyte hemoglobin in the parasite food vacuole. It is confirmed that disruption of the falcipain-2 gene led to a transient block in hemoglobin hydrolysis, and disruption of falcipain-3 gene was not possible, suggesting that protease is essential for erythrocytic parasites. On the other hand, vivapain-2, vivapain-3 and vivapain-4 are important cysteine proteases of P. vivax, which shared a number of features with falcipain-2 and falcipain-3. A recent study indicates that vivapains and aspartic protease of P. vivax works collaboratively to enhance the parasites' ability to hydrolyze host erythrocyte hemoglobin. Studies also indicate that falcipains and vivapains also hydrolyse the erythrocyte cytoskeleton proteins and involved in rupture of red blood cell. Structural and biochemical analysis of falcipains and vivapains showed that they have unique domains for specific functions. Overall, the complexes of cysteine proteases with small and macromolecular inhibitors provide structural insight to facilitate the drug design. Therefore, giving due importance to the cysteine proteases, this review will briefly focus the recent advancement in the field of cysteine proteases of human malaria parasites.

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Molekulare Erkennung in chemischen und biologischen Systemen

2015

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Strukturbasiertes Ligandendesign in der medizinischen Chemie und im Pflanzenschutz beruht auf der Identifizierung und Quantifizierung von schwachen, nichtkovalenten Wechselwirkungen und dem Verständnis der Rolle von Wasser. Ein wichtiges Werkzeug zum Abrufen von vorhandenem Wissen ist die Suche in Datenbanken von kleinen Molekülen und Proteinen. Die Erstellung eines thermodynamischen Profils zusammen mit der Röntgenstrukturanalyse und theoretischen Untersuchungen ist der Schlüssel zur Aufklärung des Energieprofils der Wasserverdrängung durch den Liganden. Biologische Bindungsstellen unterscheiden sich stark in ihrer Form, konformativen Dynamik und Polarität, weshalb verschiedene Entwicklungsstrategien für Liganden benötigt werden, wie hier anhand mehrerer Fallstudien gezeigt ist. Die Wechselwirkung zwischen Dipolen ist zu einem zentralen Baustein der molekularen Erkennung geworden. Orthogonale Wechselwirkungen, Halogenbrücken und Amid⋅⋅⋅π‐Stapelung bieten neue Möglichkeiten für innovative Leitstrukturoptimierung. Die Kombination von Untersuchungen an synthetischen Modellen und biologischen Rezeptoren ist notwendig, um verlässliche Informationen über schwache, nichtkovalente Wechselwirkungen und die Rolle von Wasser zu erlangen.

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The Structure of Chagasin in Complex with a Cysteine Protease Clarifies the Binding Mode and Evolution of an Inhibitor Family

Cited by 72 publications

References 32 publications

β-Trefoil inhibitors – from the work of Kunitz onward

β-Trefoil inhibitors – from the work of Kunitz onward

Centenary celebrations article

Molekulare Erkennung in chemischen und biologischen Systemen

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