PDBsum entry 1hkb

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protein ligands metals Protein-protein interface(s) links
Phosphotransferase PDB id
Protein chains
899 a.a. *
BGC ×4
G6P ×4
_CA ×4
Waters ×142
* Residue conservation analysis
PDB id:
Name: Phosphotransferase
Title: Crystal structure of recombinant human brain hexokinase type i complexed with glucose and glucose-6-phosphate
Structure: D-glucose 6-phosphotransferase. Chain: a, b. Synonym: hexokinase i, hexokinase type i, brain hexokinase. Engineered: yes. Other_details: crystallizes as a dimer in asymmetric unit
Source: Homo sapiens. Human. Organism_taxid: 9606. Cell_line: bl21. Organ: brain. Cellular_location: cytoplasm. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008.
2.80Å     R-factor:   0.200     R-free:   0.270
Authors: A.E.Aleshin,C.Zeng,G.P.Burenkov,H.D.Bartunik,H.J.Fromm, R.B.Honzatko
Key ref:
A.E.Aleshin et al. (1998). The mechanism of regulation of hexokinase: new insights from the crystal structure of recombinant human brain hexokinase complexed with glucose and glucose-6-phosphate. Structure, 6, 39-50. PubMed id: 9493266 DOI: 10.1016/S0969-2126(98)00006-9
01-Dec-97     Release date:   03-Jun-98    
Go to PROCHECK summary

Protein chains
Pfam   ArchSchema ?
P19367  (HXK1_HUMAN) -  Hexokinase-1
917 a.a.
899 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class: E.C.  - Hexokinase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: ATP + D-hexose = ADP + D-hexose 6-phosphate
Bound ligand (Het Group name = BGC)
corresponds exactly
D-hexose 6-phosphate
Bound ligand (Het Group name = G6P)
corresponds exactly
Molecule diagrams generated from .mol files obtained from the KEGG ftp site
 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     sperm principal piece   7 terms 
  Biological process     metabolic process   13 terms 
  Biochemical function     catalytic activity     11 terms  


DOI no: 10.1016/S0969-2126(98)00006-9 Structure 6:39-50 (1998)
PubMed id: 9493266  
The mechanism of regulation of hexokinase: new insights from the crystal structure of recombinant human brain hexokinase complexed with glucose and glucose-6-phosphate.
A.E.Aleshin, C.Zeng, G.P.Bourenkov, H.D.Bartunik, H.J.Fromm, R.B.Honzatko.
BACKGROUND: Hexokinase I is the pacemaker of glycolysis in brain tissue. The type I isozyme exhibits unique regulatory properties in that physiological levels of phosphate relieve potent inhibition by the product, glucose-6-phosphate (Gluc-6-P). The 100 kDa polypeptide chain of hexokinase I consists of a C-terminal (catalytic) domain and an N-terminal (regulatory) domain. Structures of ligated hexokinase I should provide a basis for understanding mechanisms of catalysis and regulation at an atomic level. RESULTS: The complex of human hexokinase I with glucose and Gluc-6-P (determined to 2.8 A resolution) is a dimer with twofold molecular symmetry. The N- and C-terminal domains of one monomer interact with the C- and N-terminal domains, respectively, of the symmetry-related monomer. The two domains of a monomer are connected by a single alpha helix and each have the fold of yeast hexokinase. Salt links between a possible cation-binding loop of the N-terminal domain and a loop of the C-terminal domain may be important to regulation. Each domain binds single glucose and Gluc-6-P molecules in proximity to each other. The 6-phosphoryl group of bound Gluc-6-P at the C-terminal domain occupies the putative binding site for ATP, whereas the 6-phosphoryl group at the N-terminal domain may overlap the binding site for phosphate. CONCLUSIONS: The binding synergism of glucose and Gluc-6-P probably arises out of the mutual stabilization of a common (glucose-bound) conformation of hexokinase I. Conformational changes in the N-terminal domain in response to glucose, phosphate, and/or Gluc-6-P may influence the binding of ATP to the C-terminal domain.
  Selected figure(s)  
Figure 6.
Figure 6. Stereoview of the superposition of glycerol kinase (green) onto the C-terminal domain of hexokinase (orange). The ADP molecule (red) from the glycerol kinase complex maps onto the putative active site of hexokinase I with its α-phosphate overlapping the 6-phosphoryl group of Gluc-6-P (purple). Glucose, as bound to the C-terminal domain, is in yellow. The asterisk marks loop 532–537 of hexokinase I. The corresponding loop of glycerol kinase does not interact with the phosphoryl groups of ADP. The magnesium cation associated with ADP in the glycerol kinase complex (not shown here for clarity), overlaps the pyranose ring of Gluc-6-P. (The illustration was generated with MOLSCRIPT [54].)
  The above figure is reprinted by permission from Cell Press: Structure (1998, 6, 39-50) copyright 1998.  
  Figure was selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
18509164 N.Nakamura, A.Miranda-Vizuete, K.Miki, C.Mori, and E.M.Eddy (2008).
Cleavage of disulfide bonds in mouse spermatogenic cell-specific type 1 hexokinase isozyme is associated with increased hexokinase activity and initiation of sperm motility.
  Biol Reprod, 79, 537-545.  
18260108 P.Kuser, F.Cupri, L.Bleicher, and I.Polikarpov (2008).
Crystal structure of yeast hexokinase PI in complex with glucose: A classical "induced fit" example revised.
  Proteins, 72, 731-740.
PDB code: 3b8a
17277311 E.E.Kooijman, D.P.Tieleman, C.Testerink, T.Munnik, D.T.Rijkers, K.N.Burger, and Kruijff (2007).
An electrostatic/hydrogen bond switch as the basis for the specific interaction of phosphatidic acid with proteins.
  J Biol Chem, 282, 11356-11364.  
17322968 E.J.Jeong, K.Park, H.A.Joung, C.S.Lee, D.W.Seol, B.H.Chung, and M.Kim (2007).
Detection of glucose-induced conformational change in hexokinase II using fluorescence complementation assay.
  Biotechnol Lett, 29, 797-802.  
17229727 H.Nishimasu, S.Fushinobu, H.Shoun, and T.Wakagi (2007).
Crystal structures of an ATP-dependent hexokinase with broad substrate specificity from the hyperthermophilic archaeon Sulfolobus tokodaii.
  J Biol Chem, 282, 9923-9931.
PDB codes: 2e2n 2e2o 2e2p 2e2q
17914238 P.Khodade, S.Malhotra, N.Kumar, M.S.Iyengar, N.Balakrishnan, and N.Chandra (2007).
Cytoview: development of a cell modelling framework.
  J Biosci, 32, 965-977.  
17869163 V.L.Schramm (2007).
Binding isotope effects: boon and bane.
  Curr Opin Chem Biol, 11, 529-536.  
16892082 R.B.Robey, and N.Hay (2006).
Mitochondrial hexokinases, novel mediators of the antiapoptotic effects of growth factors and Akt.
  Oncogene, 25, 4683-4696.  
15774882 C.Ingram-Smith, A.Gorrell, S.H.Lawrence, P.Iyer, K.Smith, and J.G.Ferry (2005).
Characterization of the acetate binding pocket in the Methanosarcina thermophila acetate kinase.
  J Bacteriol, 187, 2386-2394.  
16166083 D.A.Skaff, C.S.Kim, H.J.Tsai, R.B.Honzatko, and H.J.Fromm (2005).
Glucose 6-phosphate release of wild-type and mutant human brain hexokinases from mitochondria.
  J Biol Chem, 280, 38403-38409.  
16216072 J.A.Endrizzi, H.Kim, P.M.Anderson, and E.P.Baldwin (2005).
Mechanisms of product feedback regulation and drug resistance in cytidine triphosphate synthetases from the structure of a CTP-inhibited complex.
  Biochemistry, 44, 13491-13499.
PDB code: 2ad5
16233797 S.Kawai, T.Mukai, S.Mori, B.Mikami, and K.Murata (2005).
Hypothesis: structures, evolution, and ancestor of glucose kinases in the hexokinase family.
  J Biosci Bioeng, 99, 320-330.  
15239057 D.Hoffmeister, and J.S.Thorson (2004).
Mechanistic implications of Escherichia coli galactokinase structure-based engineering.
  Chembiochem, 5, 989-992.  
15016359 K.Kamata, M.Mitsuya, T.Nishimura, J.Eiki, and Y.Nagata (2004).
Structural basis for allosteric regulation of the monomeric allosteric enzyme human glucokinase.
  Structure, 12, 429-438.
PDB codes: 1v4s 1v4t
15377666 T.Mukai, S.Kawai, S.Mori, B.Mikami, and K.Murata (2004).
Crystal structure of bacterial inorganic polyphosphate/ATP-glucomannokinase. Insights into kinase evolution.
  J Biol Chem, 279, 50591-50600.
PDB code: 1woq
15466045 V.V.Lunin, Y.Li, J.D.Schrag, P.Iannuzzi, M.Cygler, and A.Matte (2004).
Crystal structures of Escherichia coli ATP-dependent glucokinase and its complex with glucose.
  J Bacteriol, 186, 6915-6927.
PDB codes: 1q18 1sz2
11512153 C.L.Verlinde, V.Hannaert, C.Blonski, M.Willson, J.J.Périé, L.A.Fothergill-Gilmore, F.R.Opperdoes, M.H.Gelb, W.G.Hol, and P.A.Michels (2001).
Glycolysis as a target for the design of new anti-trypanosome drugs.
  Drug Resist Updat, 4, 50-65.  
10387081 A.E.Aleshin, M.Malfois, X.Liu, C.S.Kim, H.J.Fromm, R.B.Honzatko, M.H.Koch, and D.I.Svergun (1999).
Nonaggregating mutant of recombinant human hexokinase I exhibits wild-type kinetics and rod-like conformations in solution.
  Biochemistry, 38, 8359-8366.  
10574795 C.Rosano, E.Sabini, M.Rizzi, D.Deriu, G.Murshudov, M.Bianchi, G.Serafini, M.Magnani, and M.Bolognesi (1999).
Binding of non-catalytic ATP to human hexokinase I highlights the structural components for enzyme-membrane association control.
  Structure, 7, 1427-1437.
PDB code: 1qha
10347146 H.Ardehali, R.L.Printz, R.R.Whitesell, J.M.May, and D.K.Granner (1999).
Functional interaction between the N- and C-terminal halves of human hexokinase II.
  J Biol Chem, 274, 15986-15989.  
10666587 P.R.Kuser, A.M.Golubev, and I.Polikarpov (1999).
Crystallization and preliminary crystal analysis of yeast hexokinase PI and PII.
  Acta Crystallogr D Biol Crystallogr, 55, 2047-2048.  
9890959 R.B.Calder, R.S.Williams, G.Ramaswamy, C.O.Rock, E.Campbell, S.E.Unkles, J.R.Kinghorn, and S.Jackowski (1999).
Cloning and characterization of a eukaryotic pantothenate kinase gene (panK) from Aspergillus nidulans.
  J Biol Chem, 274, 2014-2020.  
10531306 X.Liu, C.S.Kim, F.T.Kurbanov, R.B.Honzatko, and H.J.Fromm (1999).
Dual mechanisms for glucose 6-phosphate inhibition of human brain hexokinase.
  J Biol Chem, 274, 31155-31159.  
9665168 A.M.Mulichak, J.E.Wilson, K.Padmanabhan, and R.M.Garavito (1998).
The structure of mammalian hexokinase-1.
  Nat Struct Biol, 5, 555-560.
PDB codes: 1bdg 1bg3
9677378 T.Y.Fang, O.Alechina, A.E.Aleshin, H.J.Fromm, and R.B.Honzatko (1998).
Identification of a phosphate regulatory site and a low affinity binding site for glucose 6-phosphate in the N-terminal half of human brain hexokinase.
  J Biol Chem, 273, 19548-19553.  
The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB code is shown on the right.