TY  - JOUR
AU  - Zerrad, L.
AU  - Merli, A.
AU  - Schröder, G.F.
AU  - Varga, A.
AU  - Gráczer, E.
AU  - Pernot, P.
AU  - Round, A.
AU  - Vas, M.
AU  - Bowler, M.W.
TI  - A Spring Loaded Release Mechanism Regulates Domain Movement and Catalysis in Phosphoglycerate Kinase.
JO  - The journal of biological chemistry
VL  - 286
SN  - 0021-9258
CY  - Bethesda, Md.
PB  - Soc.
M1  - PreJuSER-16685
SP  - 14040 - 14048
PY  - 2011
N1  - This work was supported in part by Hungarian National Research Grant 77978.
AB  - 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 spring-loaded release mechanism to regulate domain movement, catalysis, and efficient product release.
KW  - Adenosine Triphosphate: chemistry
KW  - Amino Acid Sequence
KW  - Animals
KW  - Binding Sites
KW  - Biophysics: methods
KW  - Catalysis
KW  - Crystallography, X-Ray: methods
KW  - Humans
KW  - Mice
KW  - Molecular Sequence Data
KW  - Phosphoglycerate Kinase: chemistry
KW  - Protein Conformation
KW  - Protein Structure, Secondary
KW  - Protein Structure, Tertiary
KW  - Scattering, Radiation
KW  - Sequence Homology, Amino Acid
KW  - Thermodynamics
KW  - Adenosine Triphosphate (NLM Chemicals)
KW  - Phosphoglycerate Kinase (NLM Chemicals)
KW  - J (WoSType)
LB  - PUB:(DE-HGF)16
C6  - pmid:21349853
C2  - pmc:PMC3077604
UR  - <Go to ISI:>//WOS:000289556200026
DO  - DOI:10.1074/jbc.M110.206813
UR  - https://juser.fz-juelich.de/record/16685
ER  -