Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 113, Issue 35, Pages 9804-9809Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1605031113
Keywords
leishmaniases; fumarate hydratase; Fe-S cluster; X-ray crystallography
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Funding
- National Institute of General Medical Sciences from the National Institutes of Health [P41 GM103403]
- NIH-Office of Research Infrastructure Programs High-End Instrumentation Grant [S10 RR029205]
- DOE Office of Science by Argonne National Laboratory [DE-AC02-06CH11357]
- Fundacao de Amparo a Pesquisa do Estado de Sao Paulo [2009/10454-3, 2011/19674-6, 2008/08262-6]
- Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP) [11/19674-6] Funding Source: FAPESP
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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 angstrom 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 bymalonate, 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.
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