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Structural Insights into the Activation and Inhibition of Histo-Aspartic Protease from Plasmodium falciparum
Histo-aspartic protease (HAP) from Plasmodium falciparum is a promising target for the development of novel antimalarial drugs. The sequence of HAP is highly similar to those of pepsin-like aspartic proteases, but one of the two catalytic aspartates, Asp32, is replaced with histidine. Crystal struct...
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| Published in: | Biochemistry (Easton) 2011-10, Vol.50 (41), p.8862-8879 |
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| container_end_page | 8879 |
| container_issue | 41 |
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| container_title | Biochemistry (Easton) |
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| creator | Bhaumik, Prasenjit Xiao, Huogen Hidaka, Koushi Gustchina, Alla Kiso, Yoshiaki Yada, Rickey Y Wlodawer, Alexander |
| description | Histo-aspartic protease (HAP) from Plasmodium falciparum is a promising target for the development of novel antimalarial drugs. The sequence of HAP is highly similar to those of pepsin-like aspartic proteases, but one of the two catalytic aspartates, Asp32, is replaced with histidine. Crystal structures of the truncated zymogen of HAP and of the complex of the mature enzyme with inhibitor KNI-10395 have been determined at 2.1 and 2.5 Å resolution, respectively. As in other proplasmepsins, the propeptide of the zymogen interacts with the C-terminal domain of the enzyme, forcing the N- and C-terminal domains apart, thereby separating His32 and Asp215 and preventing formation of the mature active site. In the inhibitor complex, the enzyme forms a tight domain-swapped dimer, not previously seen in any aspartic proteases. The inhibitor is found in an unprecedented conformation resembling the letter U, stabilized by two intramolecular hydrogen bonds. Surprisingly, the location and conformation of the inhibitor are similar to those of the fragment of helix 2 comprising residues 34p–38p in the prosegments of the zymogens of gastric aspartic proteases; a corresponding helix assumes a vastly different orientation in proplasmepsins. Each inhibitor molecule is in contact with two molecules of HAP, interacting with the carboxylate group of the catalytic Asp215 of one HAP protomer through a water molecule, while also making a direct hydrogen bond to Glu278A′ of the other protomer. A comparison of the shifts in the positions of the catalytic residues in the inhibitor complex presented here with those published previously gives further hints regarding the enzymatic mechanism of HAP. |
| doi_str_mv | 10.1021/bi201118z |
| format | article |
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(ANL), Argonne, IL (United States). Advanced Photon Source (APS)</creatorcontrib><description>Histo-aspartic protease (HAP) from Plasmodium falciparum is a promising target for the development of novel antimalarial drugs. The sequence of HAP is highly similar to those of pepsin-like aspartic proteases, but one of the two catalytic aspartates, Asp32, is replaced with histidine. Crystal structures of the truncated zymogen of HAP and of the complex of the mature enzyme with inhibitor KNI-10395 have been determined at 2.1 and 2.5 Å resolution, respectively. As in other proplasmepsins, the propeptide of the zymogen interacts with the C-terminal domain of the enzyme, forcing the N- and C-terminal domains apart, thereby separating His32 and Asp215 and preventing formation of the mature active site. In the inhibitor complex, the enzyme forms a tight domain-swapped dimer, not previously seen in any aspartic proteases. The inhibitor is found in an unprecedented conformation resembling the letter U, stabilized by two intramolecular hydrogen bonds. Surprisingly, the location and conformation of the inhibitor are similar to those of the fragment of helix 2 comprising residues 34p–38p in the prosegments of the zymogens of gastric aspartic proteases; a corresponding helix assumes a vastly different orientation in proplasmepsins. Each inhibitor molecule is in contact with two molecules of HAP, interacting with the carboxylate group of the catalytic Asp215 of one HAP protomer through a water molecule, while also making a direct hydrogen bond to Glu278A′ of the other protomer. A comparison of the shifts in the positions of the catalytic residues in the inhibitor complex presented here with those published previously gives further hints regarding the enzymatic mechanism of HAP.</description><identifier>ISSN: 0006-2960</identifier><identifier>EISSN: 1520-4995</identifier><identifier>DOI: 10.1021/bi201118z</identifier><identifier>PMID: 21928835</identifier><language>eng</language><publisher>United States: American Chemical Society</publisher><subject>08 HYDROGEN ; Animals ; Aspartic Acid - chemistry ; Aspartic Acid Proteases - chemistry ; Catalytic Domain ; CRYSTAL STRUCTURE ; Crystallization ; Crystallography, X-Ray - methods ; ENZYMES ; Escherichia coli - metabolism ; HISTIDINE ; Histidine - chemistry ; Humans ; HYDROGEN ; Molecular Conformation ; ORIENTATION ; PLASMODIUM ; Plasmodium falciparum ; Plasmodium falciparum - enzymology ; Protein Folding ; Protein Structure, Tertiary ; Recombinant Fusion Proteins - chemistry ; RESIDUES ; RESOLUTION ; Swine ; TARGETS ; WATER</subject><ispartof>Biochemistry (Easton), 2011-10, Vol.50 (41), p.8862-8879</ispartof><rights>Copyright © 2011 American Chemical Society</rights><rights>2011 American Chemical Society</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a463t-f693cde8ba55e5af40e14948551d0597fb140078685e3db248e6c91d371f55b3</citedby><cites>FETCH-LOGICAL-a463t-f693cde8ba55e5af40e14948551d0597fb140078685e3db248e6c91d371f55b3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,315,786,790,891,27957,27958</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/21928835$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttps://www.osti.gov/biblio/1040912$$D View this record in Osti.gov$$Hfree_for_read</backlink></links><search><creatorcontrib>Bhaumik, Prasenjit</creatorcontrib><creatorcontrib>Xiao, Huogen</creatorcontrib><creatorcontrib>Hidaka, Koushi</creatorcontrib><creatorcontrib>Gustchina, Alla</creatorcontrib><creatorcontrib>Kiso, Yoshiaki</creatorcontrib><creatorcontrib>Yada, Rickey Y</creatorcontrib><creatorcontrib>Wlodawer, Alexander</creatorcontrib><creatorcontrib>Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)</creatorcontrib><title>Structural Insights into the Activation and Inhibition of Histo-Aspartic Protease from Plasmodium falciparum</title><title>Biochemistry (Easton)</title><addtitle>Biochemistry</addtitle><description>Histo-aspartic protease (HAP) from Plasmodium falciparum is a promising target for the development of novel antimalarial drugs. The sequence of HAP is highly similar to those of pepsin-like aspartic proteases, but one of the two catalytic aspartates, Asp32, is replaced with histidine. Crystal structures of the truncated zymogen of HAP and of the complex of the mature enzyme with inhibitor KNI-10395 have been determined at 2.1 and 2.5 Å resolution, respectively. As in other proplasmepsins, the propeptide of the zymogen interacts with the C-terminal domain of the enzyme, forcing the N- and C-terminal domains apart, thereby separating His32 and Asp215 and preventing formation of the mature active site. In the inhibitor complex, the enzyme forms a tight domain-swapped dimer, not previously seen in any aspartic proteases. The inhibitor is found in an unprecedented conformation resembling the letter U, stabilized by two intramolecular hydrogen bonds. Surprisingly, the location and conformation of the inhibitor are similar to those of the fragment of helix 2 comprising residues 34p–38p in the prosegments of the zymogens of gastric aspartic proteases; a corresponding helix assumes a vastly different orientation in proplasmepsins. Each inhibitor molecule is in contact with two molecules of HAP, interacting with the carboxylate group of the catalytic Asp215 of one HAP protomer through a water molecule, while also making a direct hydrogen bond to Glu278A′ of the other protomer. A comparison of the shifts in the positions of the catalytic residues in the inhibitor complex presented here with those published previously gives further hints regarding the enzymatic mechanism of HAP.</description><subject>08 HYDROGEN</subject><subject>Animals</subject><subject>Aspartic Acid - chemistry</subject><subject>Aspartic Acid Proteases - chemistry</subject><subject>Catalytic Domain</subject><subject>CRYSTAL STRUCTURE</subject><subject>Crystallization</subject><subject>Crystallography, X-Ray - methods</subject><subject>ENZYMES</subject><subject>Escherichia coli - metabolism</subject><subject>HISTIDINE</subject><subject>Histidine - chemistry</subject><subject>Humans</subject><subject>HYDROGEN</subject><subject>Molecular Conformation</subject><subject>ORIENTATION</subject><subject>PLASMODIUM</subject><subject>Plasmodium falciparum</subject><subject>Plasmodium falciparum - enzymology</subject><subject>Protein Folding</subject><subject>Protein Structure, Tertiary</subject><subject>Recombinant Fusion Proteins - chemistry</subject><subject>RESIDUES</subject><subject>RESOLUTION</subject><subject>Swine</subject><subject>TARGETS</subject><subject>WATER</subject><issn>0006-2960</issn><issn>1520-4995</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2011</creationdate><recordtype>article</recordtype><recordid>eNqFkcFqFTEUhoMo9lpd-AISBCkuRnMySSbZFC6l2kLBgt2HTCbTSZlJrkmmoE9v6q0XBcFV-MnHl5zzI_QayAcgFD72nhIAkD-eoA1wShqmFH-KNoQQ0VAlyBF6kfNdjYx07Dk6oqColC3foPlrSastazIzvgzZ304lYx9KxGVyeGuLvzfFx4BNGCow-d7_inHEFz6X2GzzzqTiLb5OsTiTHR5TXPD1bPISB78ueDSz9RVal5foWQ3ZvXo8j9HNp_Obs4vm6svny7PtVWOYaEszCtXawcnecO64GRlxwBSTnMNAuOrGHhghnRSSu3boKZNOWAVD28HIed8eo9O9drf2ixusC6WOp3fJLyZ919F4_fdN8JO-jfe65QQkFVXwdi-IuXidrS_OTjaG4GzRUJeogFbo5PGVFL-tLhe9-GzdPJvg4pq1okIqzoX8LylVJwFa9uB8vydtijknNx4-DUQ_VK0PVVf2zZ9THsjf3Vbg3R4wNuu7uKZQd_4P0U-Mh7F5</recordid><startdate>20111018</startdate><enddate>20111018</enddate><creator>Bhaumik, Prasenjit</creator><creator>Xiao, Huogen</creator><creator>Hidaka, Koushi</creator><creator>Gustchina, Alla</creator><creator>Kiso, Yoshiaki</creator><creator>Yada, Rickey Y</creator><creator>Wlodawer, Alexander</creator><general>American Chemical Society</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>C1K</scope><scope>F1W</scope><scope>H95</scope><scope>H97</scope><scope>L.G</scope><scope>M7N</scope><scope>OTOTI</scope><scope>5PM</scope></search><sort><creationdate>20111018</creationdate><title>Structural Insights into the Activation and Inhibition of Histo-Aspartic Protease from Plasmodium falciparum</title><author>Bhaumik, Prasenjit ; Xiao, Huogen ; Hidaka, Koushi ; Gustchina, Alla ; Kiso, Yoshiaki ; Yada, Rickey Y ; Wlodawer, Alexander</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a463t-f693cde8ba55e5af40e14948551d0597fb140078685e3db248e6c91d371f55b3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2011</creationdate><topic>08 HYDROGEN</topic><topic>Animals</topic><topic>Aspartic Acid - chemistry</topic><topic>Aspartic Acid Proteases - chemistry</topic><topic>Catalytic Domain</topic><topic>CRYSTAL STRUCTURE</topic><topic>Crystallization</topic><topic>Crystallography, X-Ray - methods</topic><topic>ENZYMES</topic><topic>Escherichia coli - metabolism</topic><topic>HISTIDINE</topic><topic>Histidine - chemistry</topic><topic>Humans</topic><topic>HYDROGEN</topic><topic>Molecular Conformation</topic><topic>ORIENTATION</topic><topic>PLASMODIUM</topic><topic>Plasmodium falciparum</topic><topic>Plasmodium falciparum - enzymology</topic><topic>Protein Folding</topic><topic>Protein Structure, Tertiary</topic><topic>Recombinant Fusion Proteins - chemistry</topic><topic>RESIDUES</topic><topic>RESOLUTION</topic><topic>Swine</topic><topic>TARGETS</topic><topic>WATER</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Bhaumik, Prasenjit</creatorcontrib><creatorcontrib>Xiao, Huogen</creatorcontrib><creatorcontrib>Hidaka, Koushi</creatorcontrib><creatorcontrib>Gustchina, Alla</creatorcontrib><creatorcontrib>Kiso, Yoshiaki</creatorcontrib><creatorcontrib>Yada, Rickey Y</creatorcontrib><creatorcontrib>Wlodawer, Alexander</creatorcontrib><creatorcontrib>Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>Environmental Sciences and Pollution Management</collection><collection>ASFA: Aquatic Sciences and Fisheries Abstracts</collection><collection>Aquatic Science & Fisheries Abstracts (ASFA) 1: Biological Sciences & Living Resources</collection><collection>Aquatic Science & Fisheries Abstracts (ASFA) 3: Aquatic Pollution & Environmental Quality</collection><collection>Aquatic Science & Fisheries Abstracts (ASFA) Professional</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>OSTI.GOV</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Biochemistry (Easton)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Bhaumik, Prasenjit</au><au>Xiao, Huogen</au><au>Hidaka, Koushi</au><au>Gustchina, Alla</au><au>Kiso, Yoshiaki</au><au>Yada, Rickey Y</au><au>Wlodawer, Alexander</au><aucorp>Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)</aucorp><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Structural Insights into the Activation and Inhibition of Histo-Aspartic Protease from Plasmodium falciparum</atitle><jtitle>Biochemistry (Easton)</jtitle><addtitle>Biochemistry</addtitle><date>2011-10-18</date><risdate>2011</risdate><volume>50</volume><issue>41</issue><spage>8862</spage><epage>8879</epage><pages>8862-8879</pages><issn>0006-2960</issn><eissn>1520-4995</eissn><notes>ObjectType-Article-1</notes><notes>SourceType-Scholarly Journals-1</notes><notes>ObjectType-Feature-2</notes><notes>content type line 23</notes><notes>FOREIGNNIHNCI</notes><notes>This project was supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. Financial support from the Natural Sciences and Engineering Research Council of Canada and the Canada Research Chairs Program is also gratefully acknowledged. Use of the Advanced Photon Source was supported by the U. S. Department of Energy, Office of Science, Office of Basic Energy Sciences, under Contract No. W-31-109-Eng-38.</notes><abstract>Histo-aspartic protease (HAP) from Plasmodium falciparum is a promising target for the development of novel antimalarial drugs. The sequence of HAP is highly similar to those of pepsin-like aspartic proteases, but one of the two catalytic aspartates, Asp32, is replaced with histidine. Crystal structures of the truncated zymogen of HAP and of the complex of the mature enzyme with inhibitor KNI-10395 have been determined at 2.1 and 2.5 Å resolution, respectively. As in other proplasmepsins, the propeptide of the zymogen interacts with the C-terminal domain of the enzyme, forcing the N- and C-terminal domains apart, thereby separating His32 and Asp215 and preventing formation of the mature active site. In the inhibitor complex, the enzyme forms a tight domain-swapped dimer, not previously seen in any aspartic proteases. The inhibitor is found in an unprecedented conformation resembling the letter U, stabilized by two intramolecular hydrogen bonds. Surprisingly, the location and conformation of the inhibitor are similar to those of the fragment of helix 2 comprising residues 34p–38p in the prosegments of the zymogens of gastric aspartic proteases; a corresponding helix assumes a vastly different orientation in proplasmepsins. Each inhibitor molecule is in contact with two molecules of HAP, interacting with the carboxylate group of the catalytic Asp215 of one HAP protomer through a water molecule, while also making a direct hydrogen bond to Glu278A′ of the other protomer. A comparison of the shifts in the positions of the catalytic residues in the inhibitor complex presented here with those published previously gives further hints regarding the enzymatic mechanism of HAP.</abstract><cop>United States</cop><pub>American Chemical Society</pub><pmid>21928835</pmid><doi>10.1021/bi201118z</doi><tpages>18</tpages><oa>free_for_read</oa></addata></record> |
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| source | American Chemical Society:Jisc Collections:American Chemical Society Read & Publish Agreement 2022-2024 (Reading list) |
| subjects | 08 HYDROGEN Animals Aspartic Acid - chemistry Aspartic Acid Proteases - chemistry Catalytic Domain CRYSTAL STRUCTURE Crystallization Crystallography, X-Ray - methods ENZYMES Escherichia coli - metabolism HISTIDINE Histidine - chemistry Humans HYDROGEN Molecular Conformation ORIENTATION PLASMODIUM Plasmodium falciparum Plasmodium falciparum - enzymology Protein Folding Protein Structure, Tertiary Recombinant Fusion Proteins - chemistry RESIDUES RESOLUTION Swine TARGETS WATER |
| title | Structural Insights into the Activation and Inhibition of Histo-Aspartic Protease from Plasmodium falciparum |
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