1lf3: Difference between revisions

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CRYSTAL STRUCTURE OF PLASMEPSIN II FROM P FALCIPARUM IN COMPLEX WITH INHIBITOR EH58

OverviewOverview

Malaria remains a human disease of global significance and a major cause of high infant mortality in endemic nations. Parasites of the genus Plasmodium cause the disease by degrading human hemoglobin as a source of amino acids for their growth and maturation. Hemoglobin degradation is initiated by aspartic proteases, termed plasmepsins, with a cleavage at the alpha-chain between residues Phe33 and Leu34. Plasmepsin II is one of the four catalytically active plasmepsins that has been identified in the food vacuole of Plasmodium falciparum. Novel crystal structures of uncomplexed plasmepsin II as well as the complex with a potent inhibitor have been refined with data extending to resolution limits of 1.9A and 2.7A, and to R factors of 17% and 18%, respectively. The inhibitor, N-(3-[(2-benzo[1,3]dioxol-5-yl-ethyl)[3-(1-methyl-3-oxo-1,3-dihydro-isoind ol-2-yl)-propionyl]-amino]-1-benzyl-2-(hydroxypropyl)-4-benzyloxy-3,5-dime thoxy-benzamide, belongs to a family of potent non-peptidic inhibitors that have large P1' groups. Such inhibitors could not be modeled into the binding cavity of the structure of plasmepsin II in complex with pepstatin A. Our structures reveal that the binding cavities of the new complex and uncomplexed plasmepsin II are considerably more open than that of the pepstatin A complex, allowing for larger heterocyclic groups in the P1', P2' and P2 positions. Both complexed and uncomplexed plasmepsin II crystallized in space group P2, with one monomer in the asymmetric unit. The structures show extensive interlocking of monomers around the crystallographic axis of symmetry, with areas in excess of 2300A(2) buried at the interface, and a loop of one monomer interacting with the binding cavity of the 2-fold related monomer. Electron density for this loop is only fully ordered in the complexed structure.

About this StructureAbout this Structure

1LF3 is a Single protein structure of sequence from Plasmodium falciparum with as ligand. Active as Plasmepsin II, with EC number 3.4.23.39 Full crystallographic information is available from OCA.

ReferenceReference

Novel uncomplexed and complexed structures of plasmepsin II, an aspartic protease from Plasmodium falciparum., Asojo OA, Gulnik SV, Afonina E, Yu B, Ellman JA, Haque TS, Silva AM, J Mol Biol. 2003 Mar 14;327(1):173-81. PMID:12614616

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-[[Image:1lf3.gif|left|200px]]<br />
+[[Image:1lf3.gif|left|200px]]<br /><applet load="1lf3" size="350" color="white" frame="true" align="right" spinBox="true"
-<applet load="1lf3" size="450" color="white" frame="true" align="right" spinBox="true"
 caption="1lf3, resolution 2.70&Aring;" />
 '''CRYSTAL STRUCTURE OF PLASMEPSIN II FROM P FALCIPARUM IN COMPLEX WITH INHIBITOR EH58'''<br />
 ==Overview==
-Malaria remains a human disease of global significance and a major cause, of high infant mortality in endemic nations. Parasites of the genus, Plasmodium cause the disease by degrading human hemoglobin as a source of, amino acids for their growth and maturation. Hemoglobin degradation is, initiated by aspartic proteases, termed plasmepsins, with a cleavage at, the alpha-chain between residues Phe33 and Leu34. Plasmepsin II is one of, the four catalytically active plasmepsins that has been identified in the, food vacuole of Plasmodium falciparum. Novel crystal structures of, uncomplexed plasmepsin II as well as the complex with a potent inhibitor, have been refined with data extending to resolution limits of 1.9A and, 2.7A, and to R factors of 17% and 18%, respectively. The inhibitor, N-(3-[(2-benzo[1,3]dioxol-5-yl-ethyl)[3-(1-methyl-3-oxo-1,3-dihydro-isoind, ol-2-yl)-propionyl]-amino]-1-benzyl-2-(hydroxypropyl)-4-benzyloxy-3,5-dime, thoxy-benzamide, belongs to a family of potent non-peptidic inhibitors, that have large P1' groups. Such inhibitors could not be modeled into the, binding cavity of the structure of plasmepsin II in complex with pepstatin, A. Our structures reveal that the binding cavities of the new complex and, uncomplexed plasmepsin II are considerably more open than that of the, pepstatin A complex, allowing for larger heterocyclic groups in the P1', P2' and P2 positions. Both complexed and uncomplexed plasmepsin II, crystallized in space group P2, with one monomer in the asymmetric unit., The structures show extensive interlocking of monomers around the, crystallographic axis of symmetry, with areas in excess of 2300A(2) buried, at the interface, and a loop of one monomer interacting with the binding, cavity of the 2-fold related monomer. Electron density for this loop is, only fully ordered in the complexed structure.
+Malaria remains a human disease of global significance and a major cause of high infant mortality in endemic nations. Parasites of the genus Plasmodium cause the disease by degrading human hemoglobin as a source of amino acids for their growth and maturation. Hemoglobin degradation is initiated by aspartic proteases, termed plasmepsins, with a cleavage at the alpha-chain between residues Phe33 and Leu34. Plasmepsin II is one of the four catalytically active plasmepsins that has been identified in the food vacuole of Plasmodium falciparum. Novel crystal structures of uncomplexed plasmepsin II as well as the complex with a potent inhibitor have been refined with data extending to resolution limits of 1.9A and 2.7A, and to R factors of 17% and 18%, respectively. The inhibitor, N-(3-[(2-benzo[1,3]dioxol-5-yl-ethyl)[3-(1-methyl-3-oxo-1,3-dihydro-isoind ol-2-yl)-propionyl]-amino]-1-benzyl-2-(hydroxypropyl)-4-benzyloxy-3,5-dime thoxy-benzamide, belongs to a family of potent non-peptidic inhibitors that have large P1' groups. Such inhibitors could not be modeled into the binding cavity of the structure of plasmepsin II in complex with pepstatin A. Our structures reveal that the binding cavities of the new complex and uncomplexed plasmepsin II are considerably more open than that of the pepstatin A complex, allowing for larger heterocyclic groups in the P1', P2' and P2 positions. Both complexed and uncomplexed plasmepsin II crystallized in space group P2, with one monomer in the asymmetric unit. The structures show extensive interlocking of monomers around the crystallographic axis of symmetry, with areas in excess of 2300A(2) buried at the interface, and a loop of one monomer interacting with the binding cavity of the 2-fold related monomer. Electron density for this loop is only fully ordered in the complexed structure.
 ==About this Structure==
-LF3 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Plasmodium_falciparum Plasmodium falciparum] with EH5 as [http://en.wikipedia.org/wiki/ligand ligand]. Active as [http://en.wikipedia.org/wiki/Plasmepsin_II Plasmepsin II], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.23.39 3.4.23.39] Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=1LF3 OCA].
+LF3 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Plasmodium_falciparum Plasmodium falciparum] with <scene name='pdbligand=EH5:'>EH5</scene> as [http://en.wikipedia.org/wiki/ligand ligand]. Active as [http://en.wikipedia.org/wiki/Plasmepsin_II Plasmepsin II], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.23.39 3.4.23.39] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1LF3 OCA].
 ==Reference==
@@ Line 16: / Line 15: @@
 [[Category: Single protein]]
 [[Category: Afonina, E.]]
-[[Category: Asojo, O.A.]]
+[[Category: Asojo, O A.]]
-[[Category: Ellman, J.A.]]
+[[Category: Ellman, J A.]]
-[[Category: Gulnik, S.V.]]
+[[Category: Gulnik, S V.]]
-[[Category: Haque, T.S.]]
+[[Category: Haque, T S.]]
-[[Category: Silva, A.M.]]
+[[Category: Silva, A M.]]
 [[Category: Yu, B.]]
 [[Category: EH5]]
@@ Line 27: / Line 26: @@
 [[Category: plasmodium falciparum]]
-''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Thu Nov  8 13:11:52 2007''
+''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 13:44:27 2008''