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Structures of falcipain-2 and falcipain-3 bound to small molecule inhibitors: implications for substrate specificity.

Kerr ID, Lee JH, Pandey KC, Harrison A, Sajid M, Rosenthal PJ, Brinen LS - J. Med. Chem. (2009)

Bottom Line: Falcipain-2 and falcipain-3 are critical hemoglobinases of Plasmodium falciparum, the most virulent human malaria parasite.Our structural analyses indicate that the relative shape and flexibility of the S2 pocket are affected by a number of discrete amino acid substitutions.The cumulative effect of subtle differences, including those at "gatekeeper" positions, may explain the observed kinetic differences between these two closely related enzymes.

View Article: PubMed Central - PubMed

Affiliation: Department of Cellular and Molecular Pharmacology and Department of Pathology, University of California, San Francisco, California 94158, USA.

ABSTRACT
Falcipain-2 and falcipain-3 are critical hemoglobinases of Plasmodium falciparum, the most virulent human malaria parasite. We have determined the 2.9 A crystal structure of falcipain-2 in complex with the epoxysuccinate E64 and the 2.5 A crystal structure of falcipain-3 in complex with the aldehyde leupeptin. These complexes represent the first crystal structures of plasmodial cysteine proteases with small molecule inhibitors and the first reported crystal structure of falcipain-3. Our structural analyses indicate that the relative shape and flexibility of the S2 pocket are affected by a number of discrete amino acid substitutions. The cumulative effect of subtle differences, including those at "gatekeeper" positions, may explain the observed kinetic differences between these two closely related enzymes.

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Related in: MedlinePlus

Structures of FP2 and FP3: superimposition of FP2−E64 and FP3−leupeptin with FP2 colored blue and FP3 colored yellow. Insertions are colored purple, and the N and C termini are labeled. All structure figures were prepared in PyMOL.(36)
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fig1: Structures of FP2 and FP3: superimposition of FP2−E64 and FP3−leupeptin with FP2 colored blue and FP3 colored yellow. Insertions are colored purple, and the N and C termini are labeled. All structure figures were prepared in PyMOL.(36)

Mentions: The Dali server(12) identifies cruzain, the major cysteine protease of Trypanosoma cruzi, as the parasitic homologue with the closest structural identity to both FP2 and FP3. All three share the common and well-characterized structural features of the two-domain papain-like fold. The core structure of the domains is essentially identical to that found in all previously determined FP2 structures,13−15 with minor variations in the insertions and loop regions. FP2 and FP3 share a high degree of structural similarity, and superimposition, using the DaliLite server,(12) matches 236 α-carbons with an rmsd of 0.8Å and a Z-score of 39.6 (Figure 1). The active site in each enzyme forms an extended, accessible cleft and is detailed in later sections.


Structures of falcipain-2 and falcipain-3 bound to small molecule inhibitors: implications for substrate specificity.

Kerr ID, Lee JH, Pandey KC, Harrison A, Sajid M, Rosenthal PJ, Brinen LS - J. Med. Chem. (2009)

Structures of FP2 and FP3: superimposition of FP2−E64 and FP3−leupeptin with FP2 colored blue and FP3 colored yellow. Insertions are colored purple, and the N and C termini are labeled. All structure figures were prepared in PyMOL.(36)
© Copyright Policy - open-access - ccc-price
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2651692&req=5

fig1: Structures of FP2 and FP3: superimposition of FP2−E64 and FP3−leupeptin with FP2 colored blue and FP3 colored yellow. Insertions are colored purple, and the N and C termini are labeled. All structure figures were prepared in PyMOL.(36)
Mentions: The Dali server(12) identifies cruzain, the major cysteine protease of Trypanosoma cruzi, as the parasitic homologue with the closest structural identity to both FP2 and FP3. All three share the common and well-characterized structural features of the two-domain papain-like fold. The core structure of the domains is essentially identical to that found in all previously determined FP2 structures,13−15 with minor variations in the insertions and loop regions. FP2 and FP3 share a high degree of structural similarity, and superimposition, using the DaliLite server,(12) matches 236 α-carbons with an rmsd of 0.8Å and a Z-score of 39.6 (Figure 1). The active site in each enzyme forms an extended, accessible cleft and is detailed in later sections.

Bottom Line: Falcipain-2 and falcipain-3 are critical hemoglobinases of Plasmodium falciparum, the most virulent human malaria parasite.Our structural analyses indicate that the relative shape and flexibility of the S2 pocket are affected by a number of discrete amino acid substitutions.The cumulative effect of subtle differences, including those at "gatekeeper" positions, may explain the observed kinetic differences between these two closely related enzymes.

View Article: PubMed Central - PubMed

Affiliation: Department of Cellular and Molecular Pharmacology and Department of Pathology, University of California, San Francisco, California 94158, USA.

ABSTRACT
Falcipain-2 and falcipain-3 are critical hemoglobinases of Plasmodium falciparum, the most virulent human malaria parasite. We have determined the 2.9 A crystal structure of falcipain-2 in complex with the epoxysuccinate E64 and the 2.5 A crystal structure of falcipain-3 in complex with the aldehyde leupeptin. These complexes represent the first crystal structures of plasmodial cysteine proteases with small molecule inhibitors and the first reported crystal structure of falcipain-3. Our structural analyses indicate that the relative shape and flexibility of the S2 pocket are affected by a number of discrete amino acid substitutions. The cumulative effect of subtle differences, including those at "gatekeeper" positions, may explain the observed kinetic differences between these two closely related enzymes.

Show MeSH
Related in: MedlinePlus