Crystal structure of an Fe-S cluster-containing fumarate hydratase enzyme from Leishmania major reveals a unique protein fold

Feliciano, Patricia R.; Drennan, Catherine L.; Nonato, M. Cristina

doi:10.1073/pnas.1605031113

Title: Crystal structure of an Fe-S cluster-containing fumarate hydratase enzyme from Leishmania major reveals a unique protein fold

Journal Article · Mon Aug 15 00:00:00 EDT 2016 · Proceedings of the National Academy of Sciences of the United States of America

DOI:https://doi.org/10.1073/pnas.1605031113· OSTI ID:1330258

^[1]; Drennan, Catherine L. ^[2]; Nonato, M. Cristina ^[3]

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.

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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

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Cited by: 11 works

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59 BASIC BIOLOGICAL SCIENCES
leishmaniases
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Fe-S cluster
X-ray crystallography

Title: Crystal structure of an Fe-S cluster-containing fumarate hydratase enzyme from Leishmania major reveals a unique protein fold

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