Crystal structure of an Fe-S cluster-containing fumarate hydratase enzyme from Leishmania major reveals a unique protein fold
- Univ. de Sao Paulo (Brazil); Massachusetts Inst. of Technology (MIT), Cambridge, MA (United States)
- Massachusetts Inst. of Technology (MIT), Cambridge, MA (United States)
- Univ. de Sao Paulo (Brazil)
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. Altogether, 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.
- Research Organization:
- Argonne National Lab. (ANL), Argonne, IL (United States)
- Sponsoring Organization:
- USDOE Office of Science (SC), Basic Energy Sciences (BES). Scientific User Facilities Division; National Inst. of General Medical Sciences from the National Inst. of Health; NIH-Office of Research Infrastructure Programs High-End Instrumentation; Fundação de Amparo a Pesquisa do Estado de São Paulo
- Grant/Contract Number:
- AC02-06CH11357; P41 GM103403; S10 RR029205; 2009/10454-3; 2011/19674-6; 2008/08262-6
- OSTI ID:
- 1330258
- Journal Information:
- Proceedings of the National Academy of Sciences of the United States of America, Vol. 113, Issue 35; ISSN 0027-8424
- Publisher:
- National Academy of SciencesCopyright Statement
- Country of Publication:
- United States
- Language:
- ENGLISH
Web of Science
Structural, biochemical and biophysical characterization of recombinant human fumarate hydratase
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journal | March 2019 |
Protein structure determination using metagenome sequence data
|
journal | January 2017 |
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