A 1.8 Å resolution structure of pig muscle 3-phosphoglycerate kinase with bound MgADP and 3-phosphoglycerate in open conformation: new insight into the role of the nucleotide in domain closure11Edited by R. Huber

Szilágyi, Andrea N.; Ghosh, Minakshi; Garman, Elspeth F.; Vas, Mária

doi:10.1006/jmbi.2000.4294

Cited by 58 publications

(72 citation statements)

References 31 publications

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“…2C). This conformation is very similar to previously observed crystal structures of open forms of PGK from various species (8,9,39). Comparison of the structures of these half-open binary complexes with the open structure of apo-PGK shows how binding of 3PG prepares the enzyme for catalysis.…”

Section: Solution Structure Of Apo-pgk and Domain Movements Insupporting

confidence: 87%

A Spring-loaded Release Mechanism Regulates Domain Movement and Catalysis in Phosphoglycerate Kinase

Zerrad

Merli

Schröder

et al. 2011

Journal of Biological Chemistry

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105

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Phosphoglycerate kinase (PGK) is the enzyme responsible for the first ATP-generating step of glycolysis and has been implicated extensively in oncogenesis and its development. Solution small angle x-ray scattering (SAXS) data, in combination with crystal structures of the enzyme in complex with substrate and product analogues, reveal a new conformation for the resting state of the enzyme and demonstrate the role of substrate binding in the preparation of the enzyme for domain closure. Comparison of the x-ray scattering curves of the enzyme in different states with crystal structures has allowed the complete reaction cycle to be resolved both structurally and temporally. The enzyme appears to spend most of its time in a fully open conformation with short periods of closure and catalysis, thereby allowing the rapid diffusion of substrates and products in and out of the binding sites. Analysis of the open apoenzyme structure, defined through deformable elastic network refinement against the SAXS data, suggests that interactions in a mostly buried hydrophobic region may favor the open conformation. This patch is exposed on domain closure, making the open conformation more thermodynamically stable. Ionic interactions act to maintain the closed conformation to allow catalysis. The short time PGK spends in the closed conformation and its strong tendency to rest in an open conformation imply a springloaded release mechanism to regulate domain movement, catalysis, and efficient product release. Phosphoglycerate kinase (PGK)2 catalyzes the transfer of phosphate from 1,3-bisphosphoglycerate (1,3BPG) to ADP in the first ATP-generating step of the glycolytic pathway. As a major controller of flux through the pathway, PGK is a viable target for drugs against anaerobic pathogens, such as Trypanosoma and Plasmodium species, which depend solely on glycolysis for energy metabolism (1). In addition to its metabolic role, the phosphoryl transfer activity of PGK is important in the processing of antiretroviral prodrugs that take the form of L-nucleoside analogues (2). The rate-limiting step in the in vivo activation of such compounds has been demonstrated to be the addition of a third phosphate by PGK (3). A third activity of PGK is as a signaling molecule in chordates. It is integral in the response to hypoxia, when it is secreted from the cell and inhibits angiogenesis through a disulfide reductase activity that activates plasminogen autoproteolytic activity, producing angiostatin (4). This activity apparently uses the same mechanism as the normal metabolic reaction and can be inhibited competitively by 3-phosphoglycerate (3PG) or ADP (5). Consequently, PGK has a crucial role in oncogenesis and its development.PGK is composed of two similarly sized domains, both with Rossmann fold topology, termed the N-terminal domain, which binds the phosphoglycerate species 3PG and 1,3BPG, and the C-terminal domain, which binds the nucleotides ADP and ATP. In early crystal structures of PGK (6 -9), it was apparent that this state of the enzyme ...

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Section: Solution Structure Of Apo-pgk and Domain Movements Insupporting

confidence: 87%

A Spring-loaded Release Mechanism Regulates Domain Movement and Catalysis in Phosphoglycerate Kinase

Zerrad

Merli

Schröder

et al. 2011

Journal of Biological Chemistry

Self Cite

105

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show abstract

“…For phosphoglycerate kinase, domain closure may sequester substrates and exclude water so that the appropriate acceptor group is phosphorylated by ATP. 15 Crystallographic studies on the triosephosphate isomerases from chicken muscle and yeast show that residues 168-177 leave the active site open to solvent, but close down on the bound substrate, dihydroxyacetone phosphate. This loop moves by 10 Å toward the active site as the substrate binds and may prevent unwanted side reactions with water, yielding methylglyoxal.…”

Section: * Corresponding Authorsmentioning

confidence: 99%

Dihydroorotase from Escherichia coli: Loop Movement and Cooperativity between Subunits

Chan

Guss

et al. 2005

Journal of Molecular Biology

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“…Together, these studies have led to a detailed view of the regions of conformational change upon binding and domain closure. 17,20 Previously, we reported the NMR assignment of the backbone resonances of gsPGK 21 in its ligandfree form and showed that the enzyme would form a stable AlF 4 − complex with 3PG and ADP 5 (Fig. 1c).…”

Section: Introductionmentioning

confidence: 96%

“…The crystal structure of gsPGK in the ADP-bound state 16 shows that the substrate binding sites are too distant from each other to allow efficient catalysis. However, structures of PGK from a variety of species [17][18][19] and small-angle X-ray scattering data for the human enzyme 20 indicate that PGK has hinges in the interdomain region that enable the two domains to move relative to each other in solution. Substrate binding brings the equilibrium position toward a closed conformation, and binding of ADP and 3PG induces the almost complete closure of Trypanosoma brucei PGK 19 (Fig.…”

Section: Introductionmentioning

confidence: 97%

Structural Tightening and Interdomain Communication in the Catalytic Cycle of Phosphoglycerate Kinase

Marston¹,

Cliff²,

Reed³

et al. 2010

Journal of Molecular Biology

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A 1.8 Å resolution structure of pig muscle 3-phosphoglycerate kinase with bound MgADP and 3-phosphoglycerate in open conformation: new insight into the role of the nucleotide in domain closure11Edited by R. Huber

Cited by 58 publications

References 31 publications

A Spring-loaded Release Mechanism Regulates Domain Movement and Catalysis in Phosphoglycerate Kinase

A Spring-loaded Release Mechanism Regulates Domain Movement and Catalysis in Phosphoglycerate Kinase

Dihydroorotase from Escherichia coli: Loop Movement and Cooperativity between Subunits

Structural Tightening and Interdomain Communication in the Catalytic Cycle of Phosphoglycerate Kinase

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