Crystal structure of an Fe-S cluster-containing fumarate hydratase enzyme from
Fumarate hydratases (FHs) are essential metabolic enzymes grouped into two classes. Here, we present the crystal structure of a class I FH, the cytosolic FH from Leishmania major, which reveals a previously undiscovered protein fold that coordinates a catalytically essential [4Fe-4S] cluster. Our 2....
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| Format: | Article |
| Language: | en_US |
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National Academy of Sciences (U.S.)
2017
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| Online Access: | http://hdl.handle.net/1721.1/108745 https://orcid.org/0000-0003-3853-115X https://orcid.org/0000-0001-5486-2755 |
| _version_ | 1811071165386457088 |
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| author | Nonato, M. Cristina Feliciano, Patricia Rosa Drennan, Catherine L. |
| author2 | Massachusetts Institute of Technology. Department of Biology |
| author_facet | Massachusetts Institute of Technology. Department of Biology Nonato, M. Cristina Feliciano, Patricia Rosa Drennan, Catherine L. |
| author_sort | Nonato, M. Cristina |
| collection | MIT |
| description | Fumarate hydratases (FHs) are essential metabolic enzymes grouped into two classes. Here, we present the crystal structure of a class I FH, the cytosolic FH from Leishmania major, which reveals a previously undiscovered protein fold that coordinates a catalytically essential [4Fe-4S] cluster. Our 2.05 Å resolution data further reveal a dimeric architecture for this FH that resembles a heart, with each lobe comprised of two domains that are arranged around the active site. Besides the active site, where the substrate S-malate is bound bidentate to the unique iron of the [4Fe-4S] cluster, other binding pockets are found near the dimeric enzyme interface, some of which are occupied by malonate, shown here to be a weak inhibitor of this enzyme. Taken together, these data provide a framework both for investigations of the class I FH catalytic mechanism and for drug design aimed at fighting neglected tropical diseases. |
| first_indexed | 2024-09-23T08:47:02Z |
| format | Article |
| id | mit-1721.1/108745 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T08:47:02Z |
| publishDate | 2017 |
| publisher | National Academy of Sciences (U.S.) |
| record_format | dspace |
| spelling | mit-1721.1/1087452022-09-30T11:14:49Z Crystal structure of an Fe-S cluster-containing fumarate hydratase enzyme from Nonato, M. Cristina Feliciano, Patricia Rosa Drennan, Catherine L. Massachusetts Institute of Technology. Department of Biology Massachusetts Institute of Technology. Department of Chemistry Feliciano, Patricia Rosa Drennan, Catherine L. Fumarate hydratases (FHs) are essential metabolic enzymes grouped into two classes. Here, we present the crystal structure of a class I FH, the cytosolic FH from Leishmania major, which reveals a previously undiscovered protein fold that coordinates a catalytically essential [4Fe-4S] cluster. Our 2.05 Å resolution data further reveal a dimeric architecture for this FH that resembles a heart, with each lobe comprised of two domains that are arranged around the active site. Besides the active site, where the substrate S-malate is bound bidentate to the unique iron of the [4Fe-4S] cluster, other binding pockets are found near the dimeric enzyme interface, some of which are occupied by malonate, shown here to be a weak inhibitor of this enzyme. Taken together, these data provide a framework both for investigations of the class I FH catalytic mechanism and for drug design aimed at fighting neglected tropical diseases. 2017-05-08T16:45:28Z 2017-05-08T16:45:28Z 2016-08 2016-03 Article http://purl.org/eprint/type/JournalArticle 0027-8424 1091-6490 http://hdl.handle.net/1721.1/108745 Feliciano, Patricia R.; Drennan, Catherine L. and Nonato, M. Cristina. “Crystal Structure of an Fe-S Cluster-Containing Fumarate Hydratase Enzyme fromLeishmania Majorreveals a Unique Protein Fold.” Proceedings of the National Academy of Sciences 113, no. 35 (August 2016): 9804–9809. © 2016 National Academy of Sciences https://orcid.org/0000-0003-3853-115X https://orcid.org/0000-0001-5486-2755 en_US http://dx.doi.org/10.1073/pnas.1605031113 Proceedings of the National Academy of Sciences Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use. application/pdf National Academy of Sciences (U.S.) PNAS |
| spellingShingle | Nonato, M. Cristina Feliciano, Patricia Rosa Drennan, Catherine L. Crystal structure of an Fe-S cluster-containing fumarate hydratase enzyme from |
| title | Crystal structure of an Fe-S cluster-containing fumarate hydratase enzyme from |
| title_full | Crystal structure of an Fe-S cluster-containing fumarate hydratase enzyme from |
| title_fullStr | Crystal structure of an Fe-S cluster-containing fumarate hydratase enzyme from |
| title_full_unstemmed | Crystal structure of an Fe-S cluster-containing fumarate hydratase enzyme from |
| title_short | Crystal structure of an Fe-S cluster-containing fumarate hydratase enzyme from |
| title_sort | crystal structure of an fe s cluster containing fumarate hydratase enzyme from |
| url | http://hdl.handle.net/1721.1/108745 https://orcid.org/0000-0003-3853-115X https://orcid.org/0000-0001-5486-2755 |
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