Structural view of the regulatory subunit of aspartate kinase from Mycobacterium tuberculosis

Yang, Qingzhu; Yu, Kun; Yan, Liming; Li, Yuanyuan; Chen, Cheng; Li, Xuemei

doi:10.1007/s13238-011-1094-2

Cited by 12 publications

(13 citation statements)

References 30 publications

(52 reference statements)

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“…UgpB was also reported to be involved in the Tat pathway, which is important for the virulence and physiology of several bacterial pathogens . Thus, in addition to several other anti‐TB candidate proteins that have been demonstrated to be essential for the in vitro growth of M. tuberculosis and whose structures were previously determined by our group , UgpB can be considered as another viable target for the development of new anti‐TB agents.…”

Section: Discussionmentioning

confidence: 83%

Structural analysis of Mycobacterium tuberculosis ATP‐binding cassette transporter subunit UgpB reveals specificity for glycerophosphocholine

et al. 2013

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Tuberculosis (TB), caused by Mycobacterium tuberculosis, is one of the most devastating human diseases, and is responsible for ~ 2 million deaths worldwide each year. The nutritional requirements for the growth of mycobacteria have been extensively studied since the discovery of M. tuberculosis, but the essential nutrients for M. tuberculosis inside the human host and the identity of the corresponding transporters remain unknown. The UgpABCE transporter of M. tuberculosis is one of five putative permeases for carbohydrate uptake, and is genetically predicted to be an sn‐glycerol 3‐phosphate importer. We have determined the 1.5‐Å crystal structure of M. tuberculosis UgpB, which has been reported to be a promising vaccine candidate against TB. M. tuberculosis UgpB showed no detectable binding activity for sn‐glycerol 3‐phosphate by isothermal titration calorimetry, but instead showed a preference for glycerophosphocholine (GPC). M. tuberculosis UgpB largely resembles its Escherichia coli homolog, but with the critical Trp169 in the substrate‐binding site of E. coli UgpB replaced by Leu205. Mutation of Leu205 abolishes GPC binding, suggesting that Leu205 is a determinant of GPC binding. The work reported here not only contributes to our understanding of the carbon and phosphate sources utilized by M. tuberculosis inside the human host, but will also promote improvements in TB chemotherapy. Database Structural data are available in the Protein Data Bank database under the accession number PDB http://www.rcsb.org/pdb/search/structidSearch.do?structureId=4MFI.

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Section: Discussionmentioning

confidence: 83%

Structural analysis of Mycobacterium tuberculosis ATP‐binding cassette transporter subunit UgpB reveals specificity for glycerophosphocholine

et al. 2013

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“…Although inhibition of all AKs is achieved via the disruption of substrate and ATP-binding sites, initial conformational changes differ, and include a twist of the ACT domains relative to each other [31,32], or to the catalytic domain [33]. A similar mechanism is observed for prephenate dehydratase (PDT) in which the binding of phenylalanine leads to the tightening of the ACT-domain interface, triggering a subtle rearrangement of the whole protein and partially closing access to the distant active site [29].…”

Section: Current Opinion In Structural Biologymentioning

confidence: 99%

Allosteric ACTion: the varied ACT domains regulating enzymes of amino-acid metabolism

Lang

Cross

Mittelstädt

et al. 2014

Current Opinion in Structural Biology

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“…The ligand-binding sites for the allosteric effector(s) are typically associated with interfaces between two or more ACT domains. The underlying details of the allosteric mechanisms associated with the ACT domain are now starting to be revealed: generally, ligand binding in these sites elicits structural changes that alter the catalytic function of the remote active site (13,15,16,18,19).3-Deoxy-D-arabino-heptulosonate 7-phosphate synthase (DAH7PS) is the first enzyme of the shikimate pathway, which is responsible for the biosynthesis of the aromatic amino acids Phe, Tyr, and Trp (Fig. 1A).…”

mentioning

confidence: 99%

Engineering allosteric control to an unregulated enzyme by transfer of a regulatory domain

Cross

Allison

Dobson

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Allosteric regulation of protein function is a critical component of metabolic control. Its importance is underpinned by the diversity of mechanisms and its presence in all three domains of life. The first enzyme of the aromatic amino acid biosynthesis, 3-deoxy-Darabino-heptulosonate 7-phosphate synthase, shows remarkable variation in allosteric response and machinery, and both contemporary regulated and unregulated orthologs have been described. To examine the molecular events by which allostery can evolve, we have generated a chimeric protein by joining the catalytic domain of an unregulated 3-deoxy-D-arabino-heptulosonate 7-phosphate synthase with the regulatory domain of a regulated enzyme. We demonstrate that this simple gene fusion event on its own is sufficient to confer functional allostery to the unregulated enzyme. The fusion protein shares structural similarities with its regulated parent protein and undergoes an analogous major conformational change in response to the binding of allosteric effector tyrosine to the regulatory domain. These findings help delineate a remarkably facile mechanism for the evolution of modular allostery by domain recruitment.ACT domain | shikimate P rotein allostery, where ligand binding is coupled to a functional change at a remote site, is critical for the control of metabolism. For enzymes of key metabolic pathways, allostery allows precise control of catalysis in response to cellular demand. Although this important phenomenon was first described many years ago, it is only more recently that the molecular details that govern this precise control of enzyme function have been explored for a diverse range of protein systems (1-3). Functional change results from changes in the protein energy landscape elicited by ligand binding (4). This change in energy landscape may lead to conformational change and/or may be more subtly expressed as a change in protein molecular dynamics (5-12).The importance of protein allostery is underpinned by the observation that it is ubiquitous. As more proteins are studied in detail, one of the striking revelations is the variety of allosteric mechanisms that are used to control protein function. These mechanisms can be broadly divided into three groups that reflect the evolutionary path taken to acquire the allosteric functionality (5). In the first group, modification of existing structural features of a protein creates an allosteric site. Second, the formation of homo-and heterooligomeric assemblies may lead to the development of allosteric sites at the interface of subunits. Third, allostery may be endowed by domain fusion to create a modular protein with a distinct domain responsible for binding of the allosteric effector. A detailed understanding of this modular allostery, in which the allosteric effector binding site is associated with a discrete protein domain, offers the potential to generate engineered proteins with tailored functionality.The ACT domain has been identified as a modular regulatory unit associated with the control of a var...

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Structural view of the regulatory subunit of aspartate kinase from Mycobacterium tuberculosis

Cited by 12 publications

References 30 publications

Structural analysis of Mycobacterium tuberculosis ATP‐binding cassette transporter subunit UgpB reveals specificity for glycerophosphocholine

Structural analysis of Mycobacterium tuberculosis ATP‐binding cassette transporter subunit UgpB reveals specificity for glycerophosphocholine

Allosteric ACTion: the varied ACT domains regulating enzymes of amino-acid metabolism

Engineering allosteric control to an unregulated enzyme by transfer of a regulatory domain

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