4F1E

The Crystal Structure of a Human MitoNEET mutant with Asp 67 replaced by a Gly

Summary for 4F1E

• Entry DOI: 10.2210/pdb4f1e/pdb
• Related: 2QH7 3EW0 3LPQ 4EZF 4F28 4F2C
• Descriptor: CDGSH iron-sulfur domain-containing protein 1, FE2/S2 (INORGANIC) CLUSTER (3 entities in total)
• Functional Keywords: zinc finger cdgsh-type domain 1, mitochondrial outer membrane, metal binding protein
• Biological source: Homo sapiens (human)
• Cellular location: Mitochondrion outer membrane; Single-pass type III membrane protein: Q9NZ45
• Total number of polymer chains: 18
• Total formula weight: 163190.00

Authors

Baxter, E.I.,Zuris, J.A.,Wang, C.,Axelrod, H.L.,Cohen, A.E.,Paddock, M.L.,Nechushtai, R.,Onuchic, J.N.,Jennings, P.A. (deposition date: 2012-05-06, release date: 2012-12-26, Last modification date: 2023-09-13)

Primary citation

Baxter, E.L.,Zuris, J.A.,Wang, C.,Vo, P.L.,Axelrod, H.L.,Cohen, A.E.,Paddock, M.L.,Nechushtai, R.,Onuchic, J.N.,Jennings, P.A.
Allosteric control in a metalloprotein dramatically alters function.
Proc.Natl.Acad.Sci.USA, 110:948-953, 2013

PubMed Abstract: Metalloproteins (MPs) comprise one-third of all known protein structures. This diverse set of proteins contain a plethora of unique inorganic moieties capable of performing chemistry that would otherwise be impossible using only the amino acids found in nature. Most of the well-studied MPs are generally viewed as being very rigid in structure, and it is widely thought that the properties of the metal centers are primarily determined by the small fraction of amino acids that make up the local environment. Here we examine both theoretically and experimentally whether distal regions can influence the metal center in the diabetes drug target mitoNEET. We demonstrate that a loop (L2) 20 Å away from the metal center exerts allosteric control over the cluster binding domain and regulates multiple properties of the metal center. Mutagenesis of L2 results in significant shifts in the redox potential of the [2Fe-2S] cluster and orders of magnitude effects on the rate of [2Fe-2S] cluster transfer to an apo-acceptor protein. These surprising effects occur in the absence of any structural changes. An examination of the native basin dynamics of the protein using all-atom simulations shows that twisting in L2 controls scissoring in the cluster binding domain and results in perturbations to one of the cluster-coordinating histidines. These allosteric effects are in agreement with previous folding simulations that predicted L2 could communicate with residues surrounding the metal center. Our findings suggest that long-range dynamical changes in the protein backbone can have a significant effect on the functional properties of MPs.

PubMed: 23271805
DOI: 10.1073/pnas.1208286110

Experimental method

X-RAY DIFFRACTION (2.4 Å)