PDBsum entry 7icd

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Oxidoreductase (NAD(a)-choh(d)) PDB id
Protein chain
414 a.a. *
Waters ×66
* Residue conservation analysis
PDB id:
Name: Oxidoreductase (NAD(a)-choh(d))
Title: Regulation of an enzyme by phosphorylation at the active sit
Structure: Isocitrate dehydrogenase. Chain: a. Engineered: yes
Source: Escherichia coli. Organism_taxid: 562
Biol. unit: Dimer (from PQS)
2.40Å     R-factor:   0.179    
Authors: J.H.Hurley,A.M.Dean,J.L.Sohl,D.E.Koshlandjunior,R.M.Stroud
Key ref: J.H.Hurley et al. (1990). Regulation of an enzyme by phosphorylation at the active site. Science, 249, 1012-1016. PubMed id: 2204109 DOI: 10.1126/science.2204109
30-May-90     Release date:   15-Oct-91    
Go to PROCHECK summary

Protein chain
Pfam   ArchSchema ?
P08200  (IDH_ECOLI) -  Isocitrate dehydrogenase [NADP]
416 a.a.
414 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 1 residue position (black cross)

 Enzyme reactions 
   Enzyme class: E.C.  - Isocitrate dehydrogenase (NADP(+)).
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]

Citric acid cycle
      Reaction: Isocitrate + NADP+ = 2-oxoglutarate + CO2 + NADPH
+ NADP(+)
= 2-oxoglutarate
+ CO(2)
      Cofactor: Manganese or magnesium
Molecule diagrams generated from .mol files obtained from the KEGG ftp site
 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     cytoplasm   1 term 
  Biological process     oxidation-reduction process   4 terms 
  Biochemical function     oxidoreductase activity     6 terms  


DOI no: 10.1126/science.2204109 Science 249:1012-1016 (1990)
PubMed id: 2204109  
Regulation of an enzyme by phosphorylation at the active site.
J.H.Hurley, A.M.Dean, J.L.Sohl, D.E.Koshland, R.M.Stroud.
The isocitrate dehydrogenase of Escherichia coli is an example of a ubiquitous class of enzymes that are regulated by covalent modification. In the three-dimensional structure of the enzyme-substrate complex, isocitrate forms a hydrogen bond with Ser113, the site of regulatory phosphorylation. The structures of Asp113 and Glu113 mutants, which mimic the inactivation of the enzyme by phosphorylation, show minimal conformational changes from wild type, as in the phosphorylated enzyme. Calculations based on observed structures suggest that the change in electrostatic potential when a negative charge is introduced either by phosporylation or site-directed mutagenesis is sufficient to inactivate the enzyme. Thus, direct interaction at a ligand binding site is an alternative mechanism to induced conformational changes from an allosteric site in the regulation of protein activity by phosphorylation.

Literature references that cite this PDB file's key reference

  PubMed id Reference
20505668 J.Zheng, and Z.Jia (2010).
Structure of the bifunctional isocitrate dehydrogenase kinase/phosphatase.
  Nature, 465, 961-965.
PDB codes: 3eps 3lc6 3lcb
20513808 Z.J.Reitman, and H.Yan (2010).
Isocitrate dehydrogenase 1 and 2 mutations in cancer: alterations at a crossroads of cellular metabolism.
  J Natl Cancer Inst, 102, 932-941.  
18834307 B.Macek, M.Mann, and J.V.Olsen (2009).
Global and site-specific quantitative phosphoproteomics: principles and applications.
  Annu Rev Pharmacol Toxicol, 49, 199-221.  
18256028 A.B.Taylor, G.Hu, P.J.Hart, and L.McAlister-Henn (2008).
Allosteric motions in structures of yeast NAD+-specific isocitrate dehydrogenase.
  J Biol Chem, 283, 10872-10880.
PDB codes: 3blv 3blw 3blx
18552125 Y.Peng, C.Zhong, W.Huang, and J.Ding (2008).
Structural studies of Saccharomyces cerevesiae mitochondrial NADP-dependent isocitrate dehydrogenase in different enzymatic states reveal substantial conformational changes during the catalytic reaction.
  Protein Sci, 17, 1542-1554.
PDB codes: 2qfv 2qfw 2qfx 2qfy
17377789 C.Hildmann, D.Riester, and A.Schwienhorst (2007).
Histone deacetylases--an important class of cellular regulators with a variety of functions.
  Appl Microbiol Biotechnol, 75, 487-497.  
17289565 Z.Serber, and J.E.Ferrell (2007).
Tuning bulk electrostatics to regulate protein function.
  Cell, 128, 441-444.  
16416443 F.Imabayashi, S.Aich, L.Prasad, and L.T.Delbaere (2006).
Substrate-free structure of a monomeric NADP isocitrate dehydrogenase: an open conformation phylogenetic relationship of isocitrate dehydrogenase.
  Proteins, 63, 100-112.
PDB code: 2b0t
16284723 A.Rodríguez-Arnedo, M.Camacho, F.Llorca, and M.J.Bonete (2005).
Complete reversal of coenzyme specificity of isocitrate dehydrogenase from Haloferax volcanii.
  Protein J, 24, 259-266.  
15576556 T.K.Kim, and R.F.Colman (2005).
Ser95, Asn97, and Thr78 are important for the catalytic function of porcine NADP-dependent isocitrate dehydrogenase.
  Protein Sci, 14, 140-147.  
15263083 J.S.Pitula, K.M.Deck, S.L.Clarke, S.A.Anderson, A.Vasanthakumar, and R.S.Eisenstein (2004).
Selective inhibition of the citrate-to-isocitrate reaction of cytosolic aconitase by phosphomimetic mutation of serine-711.
  Proc Natl Acad Sci U S A, 101, 10907-10912.  
15576032 R.M.Wynn, M.Kato, M.Machius, J.L.Chuang, J.Li, D.R.Tomchick, and D.T.Chuang (2004).
Molecular mechanism for regulation of the human mitochondrial branched-chain alpha-ketoacid dehydrogenase complex by phosphorylation.
  Structure, 12, 2185-2196.
PDB codes: 1u5b 1x7w 1x7x 1x7y 1x7z 1x80
12619682 J.J.Yoon, T.Hattori, and M.Shimada (2003).
Purification and characterization of NADP-linked isocitrate dehydrogenase from the copper-tolerant wood-rotting basidiomycete Fomitopsis palustris.
  Biosci Biotechnol Biochem, 67, 114-120.  
14595395 M.E.Stroupe, H.K.Leech, D.S.Daniels, M.J.Warren, and E.D.Getzoff (2003).
CysG structure reveals tetrapyrrole-binding features and novel regulation of siroheme biosynthesis.
  Nat Struct Biol, 10, 1064-1073.
PDB codes: 1pjq 1pjs 1pjt
12468231 C.I.Holmberg, S.E.Tran, J.E.Eriksson, and L.Sistonen (2002).
Multisite phosphorylation provides sophisticated regulation of transcription factors.
  Trends Biochem Sci, 27, 619-627.  
12022879 G.S.Anand, and A.M.Stock (2002).
Kinetic basis for the stimulatory effect of phosphorylation on the methylesterase activity of CheB.
  Biochemistry, 41, 6752-6760.  
11826966 M.Fujita, H.Tamegai, T.Eguchi, and K.Kakinuma (2001).
Novel substrate specificity of designer 3-isopropylmalate dehydrogenase derived from Thermus thermophilus HB8.
  Biosci Biotechnol Biochem, 65, 2695-2700.  
11284679 S.A.Doyle, P.T.Beernink, and D.E.Koshland (2001).
Structural basis for a change in substrate specificity: crystal structure of S113E isocitrate dehydrogenase in a complex with isopropylmalate, Mg2+, and NADP.
  Biochemistry, 40, 4234-4241.
PDB code: 1hj6
11440123 S.Watanabe, Y.Takada, and N.Fukunaga (2001).
Purification and characterization of a cold-adapted isocitrate lyase and a malate synthase from Colwellia maris, a psychrophilic bacterium.
  Biosci Biotechnol Biochem, 65, 1095-1103.  
11679744 Y.Yasutake, S.Watanabe, M.Yao, Y.Takada, N.Fukunaga, and I.Tanaka (2001).
Crystallization and preliminary X-ray diffraction studies of monomeric isocitrate dehydrogenase by the MAD method using Mn atoms.
  Acta Crystallogr D Biol Crystallogr, 57, 1682-1685.  
10966457 A.M.Stock, V.L.Robinson, and P.N.Goudreau (2000).
Two-component signal transduction.
  Annu Rev Biochem, 69, 183-215.  
9876124 A.Tholey, A.Lindemann, V.Kinzel, and J.Reed (1999).
Direct effects of phosphorylation on the preferred backbone conformation of peptides: a nuclear magnetic resonance study.
  Biophys J, 76, 76-87.  
10398926 C.B.Post, B.S.Gaul, E.Z.Eisenmesser, and M.L.Schneider (1999).
NMR structure of phospho-tyrosine signaling complexes.
  Med Res Rev, 19, 295-305.  
10588700 J.Kim, J.M.Lee, P.E.Branton, and J.Pelletier (1999).
Modification of EWS/WT1 functional properties by phosphorylation.
  Proc Natl Acad Sci U S A, 96, 14300-14305.  
10360181 R.Gaudet, J.R.Savage, J.N.McLaughlin, B.M.Willardson, and P.B.Sigler (1999).
A molecular mechanism for the phosphorylation-dependent regulation of heterotrimeric G proteins by phosducin.
  Mol Cell, 3, 649-660.
PDB codes: 1b9x 1b9y
10477256 Y.Xu, G.Bhargava, H.Wu, G.Loeber, and L.Tong (1999).
Crystal structure of human mitochondrial NAD(P)+-dependent malic enzyme: a new class of oxidative decarboxylases.
  Structure, 7, R877-R889.  
9891796 A.J.Cozzone (1998).
Regulation of acetate metabolism by protein phosphorylation in enteric bacteria.
  Annu Rev Microbiol, 52, 127-164.  
9783749 B.L.Stoddard, B.E.Cohen, M.Brubaker, A.D.Mesecar, and D.E.Koshland (1998).
Millisecond Laue structures of an enzyme-product complex using photocaged substrate analogs.
  Nat Struct Biol, 5, 891-897.
PDB code: 1bl5
9818266 B.L.Stoddard (1998).
New results using Laue diffraction and time-resolved crystallography.
  Curr Opin Struct Biol, 8, 612-618.  
9739088 K.Imada, K.Inagaki, H.Matsunami, H.Kawaguchi, H.Tanaka, N.Tanaka, and K.Namba (1998).
Structure of 3-isopropylmalate dehydrogenase in complex with 3-isopropylmalate at 2.0 A resolution: the role of Glu88 in the unique substrate-recognition mechanism.
  Structure, 6, 971-982.
PDB code: 1a05
9649435 S.Béraud-Dufour, S.Robineau, P.Chardin, S.Paris, M.Chabre, J.Cherfils, and B.Antonny (1998).
A glutamic finger in the guanine nucleotide exchange factor ARNO displaces Mg2+ and the beta-phosphate to destabilize GDP on ARF1.
  EMBO J, 17, 3651-3659.  
9448284 T.Kuwana, P.A.Peterson, and L.Karlsson (1998).
Exit of major histocompatibility complex class II-invariant chain p35 complexes from the endoplasmic reticulum is modulated by phosphorylation.
  Proc Natl Acad Sci U S A, 95, 1056-1061.  
9220992 B.E.Cohen, B.L.Stoddard, and D.E.Koshland (1997).
Caged NADP and NAD. Synthesis and characterization of functionally distinct caged compounds.
  Biochemistry, 36, 9035-9044.  
  9194198 B.Kobe, I.G.Jennings, C.M.House, S.C.Feil, B.J.Michell, T.Tiganis, M.W.Parker, R.G.Cotton, and B.E.Kemp (1997).
Regulation and crystallization of phosphorylated and dephosphorylated forms of truncated dimeric phenylalanine hydroxylase.
  Protein Sci, 6, 1352-1357.  
  9352899 F.S.Wang, T.S.Whittam, and R.K.Selander (1997).
Evolutionary genetics of the isocitrate dehydrogenase gene (icd) in Escherichia coli and Salmonella enterica.
  J Bacteriol, 179, 6551-6559.  
9201951 J.L.Buchbinder, C.B.Luong, M.F.Browner, and R.J.Fletterick (1997).
Partial activation of muscle phosphorylase by replacement of serine 14 with acidic residues at the site of regulatory phosphorylation.
  Biochemistry, 36, 8039-8044.  
9384566 K.Lin, P.K.Hwang, and R.J.Fletterick (1997).
Distinct phosphorylation signals converge at the catalytic center in glycogen phosphorylases.
  Structure, 5, 1511-1523.  
9151681 P.Franco, C.Iaccarino, F.Chiaradonna, A.Brandazza, C.Iavarone, M.R.Mastronicola, M.L.Nolli, and M.P.Stoppelli (1997).
Phosphorylation of human pro-urokinase on Ser138/303 impairs its receptor-dependent ability to promote myelomonocytic adherence and motility.
  J Cell Biol, 137, 779-791.  
9428712 R.Chen, A.F.Greer, and A.M.Dean (1997).
Structural constraints in protein engineering--the coenzyme specificity of Escherichia coli isocitrate dehydrogenase.
  Eur J Biochem, 250, 578-582.  
  8745412 A.M.Dean, A.K.Shiau, and D.E.Koshland (1996).
Determinants of performance in the isocitrate dehydrogenase of Escherichia coli.
  Protein Sci, 5, 341-347.  
8673602 B.L.Stoddard, A.Dean, and P.A.Bash (1996).
Combining Laue diffraction and molecular dynamics to study enzyme intermediates.
  Nat Struct Biol, 3, 590-595.  
8888067 B.L.Stoddard (1996).
Intermediate trapping and laue X-ray diffraction: potential for enzyme mechanism, dynamics, and inhibitor screening.
  Pharmacol Ther, 70, 215-256.  
  8552098 D.Parker, K.Ferreri, T.Nakajima, V.J.LaMorte, R.Evans, S.C.Koerber, C.Hoeger, and M.R.Montminy (1996).
Phosphorylation of CREB at Ser-133 induces complex formation with CREB-binding protein via a direct mechanism.
  Mol Cell Biol, 16, 694-703.  
8664264 E.Alvarez-Villafañe, J.Soler, P.del Valle, F.Busto, and Arriaga (1996).
Two NAD+-isocitrate dehydrogenase forms in Phycomyces blakesleeanus. Induction in response to acetate growth and characterization, kinetics, and regulation of both enzyme forms.
  Biochemistry, 35, 4741-4752.  
8639526 J.H.Hurley, R.Chen, and A.M.Dean (1996).
Determinants of cofactor specificity in isocitrate dehydrogenase: structure of an engineered NADP+ --> NAD+ specificity-reversal mutant.
  Biochemistry, 35, 5670-5678.
PDB code: 1iso
8608121 M.J.Brubaker, D.H.Dyer, B.Stoddard, and D.E.Koshland (1996).
Synthesis, kinetics, and structural studies of a photolabile caged isocitrate: a catalytic trigger for isocitrate dehydrogenase.
  Biochemistry, 35, 2854-2864.  
8710874 Z.Y.Zhu, and S.Karlin (1996).
Clusters of charged residues in protein three-dimensional structures.
  Proc Natl Acad Sci U S A, 93, 8350-8355.  
  8535253 A.M.Dean, and L.Dvorak (1995).
The role of glutamate 87 in the kinetic mechanism of Thermus thermophilus isopropylmalate dehydrogenase.
  Protein Sci, 4, 2156-2167.  
  7836312 B.J.Eikmanns, D.Rittmann, and H.Sahm (1995).
Cloning, sequence analysis, expression, and inactivation of the Corynebacterium glutamicum icd gene encoding isocitrate dehydrogenase and biochemical characterization of the enzyme.
  J Bacteriol, 177, 774-782.  
8548273 G.K.Farber (1995).
Laue crystallography. It's show time.
  Curr Biol, 5, 1088-1090.  
  7549867 I.J.Kurland, and S.J.Pilkis (1995).
Covalent control of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase: insights into autoregulation of a bifunctional enzyme.
  Protein Sci, 4, 1023-1037.  
  16535052 J.Olano, Arriaga, F.Busto, and J.Soler (1995).
Kinetics and Thermostability of NADP-Isocitrate Dehydrogenase from Cephalosporium acremonium.
  Appl Environ Microbiol, 61, 2326-2334.  
  7588633 K.Okazaki, and N.Sagata (1995).
The Mos/MAP kinase pathway stabilizes c-Fos by phosphorylation and augments its transforming activity in NIH 3T3 cells.
  EMBO J, 14, 5048-5059.  
  7536733 M.Suzuki, T.Sahara, J.Tsuruha, Y.Takada, and N.Fukunaga (1995).
Differential expression in Escherichia coli of the Vibrio sp. strain ABE-1 icdI and icdII genes encoding structurally different isocitrate dehydrogenase isozymes.
  J Bacteriol, 177, 2138-2142.  
8524825 R.Chen, A.Greer, and A.M.Dean (1995).
A highly active decarboxylating dehydrogenase with rationally inverted coenzyme specificity.
  Proc Natl Acad Sci U S A, 92, 11666-11670.  
  7920262 A.R.Poirrette, P.J.Artymiuk, H.M.Grindley, D.W.Rice, and P.Willett (1994).
Structural similarity between binding sites in influenza sialidase and isocitrate dehydrogenase: implications for an alternative approach to rational drug design.
  Protein Sci, 3, 1128-1130.  
7881901 J.H.Hurley, and A.M.Dean (1994).
Structure of 3-isopropylmalate dehydrogenase in complex with NAD+: ligand-induced loop closing and mechanism for cofactor specificity.
  Structure, 2, 1007-1016.
PDB code: 1hex
7877607 J.Stigare, S.Lajic, M.Holst, A.Pigon, and E.Egyházi (1994).
The salivary gland 42-kDa phosphoprotein is a single-stranded DNA-binding protein with characteristics of the epithelial casein kinase N42 in Chironomus tentans.
  Mol Cell Biochem, 141, 35-46.  
8181473 K.Miyazaki, T.Yaoi, and T.Oshima (1994).
Expression, purification, and substrate specificity of isocitrate dehydrogenase from Thermus thermophilus HB8.
  Eur J Biochem, 221, 899-903.  
  7849589 L.N.Johnson, and D.Barford (1994).
Electrostatic effects in the control of glycogen phosphorylase by phosphorylation.
  Protein Sci, 3, 1726-1730.  
  8169222 M.I.Muro-Pastor, and F.J.Florencio (1994).
NADP(+)-isocitrate dehydrogenase from the cyanobacterium Anabaena sp. strain PCC 7120: purification and characterization of the enzyme and cloning, sequencing, and disruption of the icd gene.
  J Bacteriol, 176, 2718-2726.  
7874731 Q.Xie, and A.Jiménez (1994).
Cloning and molecular analysis of two different ILV5 genes from a brewing strain of Saccharomyces cerevisiae.
  Curr Genet, 26, 398-402.  
  8392618 A.G.Albright, and F.J.Jenkins (1993).
The herpes simplex virus UL37 protein is phosphorylated in infected cells.
  J Virol, 67, 4842-4847.  
8433976 B.L.Stoddard, and D.E.Koshland (1993).
Molecular recognition analyzed by docking simulations: the aspartate receptor and isocitrate dehydrogenase from Escherichia coli.
  Proc Natl Acad Sci U S A, 90, 1146-1153.  
8381789 D.C.LaPorte (1993).
The isocitrate dehydrogenase phosphorylation cycle: regulation and enzymology.
  J Cell Biochem, 51, 14-18.  
  7682214 K.Kelly-Wintenberg, S.L.South, and T.C.Montie (1993).
Tyrosine phosphate in a- and b-type flagellins of Pseudomonas aeruginosa.
  J Bacteriol, 175, 2458-2461.  
  8514749 S.K.Drake, R.B.Bourret, L.A.Luck, M.I.Simon, and J.J.Falke (1993).
Activation of the phosphosignaling protein CheY. I. Analysis of the phosphorylated conformation by 19F NMR and protein engineering.
  J Biol Chem, 268, 13081-13088.  
7691416 T.T.Egelhoff, R.J.Lee, and J.A.Spudich (1993).
Dictyostelium myosin heavy chain phosphorylation sites regulate myosin filament assembly and localization in vivo.
  Cell, 75, 363-371.  
  1304374 A.Cortes, D.C.Emery, D.J.Halsall, R.M.Jackson, A.R.Clarke, and J.J.Holbrook (1992).
Charge balance in the alpha-hydroxyacid dehydrogenase vacuole: an acid test.
  Protein Sci, 1, 892-901.  
1585448 J.F.Allen (1992).
How does protein phosphorylation regulate photosynthesis?
  Trends Biochem Sci, 17, 12-17.  
  1545817 J.M.Nigro, R.Sikorski, S.I.Reed, and B.Vogelstein (1992).
Human p53 and CDC2Hs genes combine to inhibit the proliferation of Saccharomyces cerevisiae.
  Mol Cell Biol, 12, 1357-1365.  
  1539996 K.Miyazaki, H.Eguchi, A.Yamagishi, T.Wakagi, and T.Oshima (1992).
Molecular cloning of the isocitrate dehydrogenase gene of an extreme thermophile, Thermus thermophilus HB8.
  Appl Environ Microbiol, 58, 93-98.  
1730247 M.I.Muro-Pastor, and F.J.Florencio (1992).
Purification and properties of NADP-isocitrate dehydrogenase from the unicellular cyanobacterium Synechocystis sp. PCC 6803.
  Eur J Biochem, 203, 99.  
  1321032 M.Nishizawa, K.Okazaki, N.Furuno, N.Watanabe, and N.Sagata (1992).
The 'second-codon rule' and autophosphorylation govern the stability and activity of Mos during the meiotic cell cycle in Xenopus oocytes.
  EMBO J, 11, 2433-2446.  
1643656 T.Hunter, and M.Karin (1992).
The regulation of transcription by phosphorylation.
  Cell, 70, 375-387.  
1961703 D.Worthylake, N.D.Meadow, S.Roseman, D.I.Liao, O.Herzberg, and S.J.Remington (1991).
Three-dimensional structure of the Escherichia coli phosphocarrier protein IIIglc.
  Proc Natl Acad Sci U S A, 88, 10382-10386.
PDB code: 1f3g
1367679 J.A.Tainer, V.A.Roberts, and E.D.Getzoff (1991).
Metal-binding sites in proteins.
  Curr Opin Biotechnol, 2, 582-591.  
15336093 J.Corbin (1991).
Two lobes and a cleft.
  Curr Biol, 1, 400-401.  
  1655416 K.L.Gould, S.Moreno, D.J.Owen, S.Sazer, and P.Nurse (1991).
Phosphorylation at Thr167 is required for Schizosaccharomyces pombe p34cdc2 function.
  EMBO J, 10, 3297-3309.  
15336195 L.N.Johnson (1991).
Direct interaction or remote control?
  Curr Biol, 1, 17-19.  
2023950 M.Meng, C.Lee, M.Bagdasarian, and J.G.Zeikus (1991).
Switching substrate preference of thermophilic xylose isomerase from D-xylose to D-glucose by redesigning the substrate binding pocket.
  Proc Natl Acad Sci U S A, 88, 4015-4019.  
1661416 W.E.Farnsworth (1991).
Prostate plasma membrane receptor: a hypothesis.
  Prostate, 19, 329-352.  
  2490368 L.N.Johnson (1989).
Glycogen phosphorylase: a multifaceted enzyme.
  Carlsberg Res Commun, 54, 203-229.  
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 codes are shown on the right.