PDBsum entry 1ai3

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Oxidoreductase PDB id
Protein chain
414 a.a. *
Waters ×298
* Residue conservation analysis
PDB id:
Name: Oxidoreductase
Title: Orbital steering in the catalytic power of enzymes: small st changes with large catalytic consequences
Structure: Isocitrate dehydrogenase. Chain: a. Synonym: oxalosuccinate decarboxylase, idh. Engineered: yes
Source: Escherichia coli. Organism_taxid: 562. Cell_line: dek2004. Expressed in: escherichia coli. Expression_system_taxid: 562.
Biol. unit: Homo-Dimer (from PDB file)
1.90Å     R-factor:   0.188     R-free:   0.220
Authors: B.L.Stoddard,A.Mesecar,D.E.Koshland Junior
Key ref:
A.D.Mesecar et al. (1997). Orbital steering in the catalytic power of enzymes: small structural changes with large catalytic consequences. Science, 277, 202-206. PubMed id: 9211842 DOI: 10.1126/science.277.5323.202
30-Apr-97     Release date:   12-Nov-97    
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

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

Citric acid cycle
      Reaction: Isocitrate + NADP+ = 2-oxoglutarate + CO2 + NADPH
Bound ligand (Het Group name = ICT)
corresponds exactly
Bound ligand (Het Group name = NDO)
matches with 95.92% similarity
= 2-oxoglutarate
+ CO(2)
      Cofactor: Mn(2+) or Mg(2+)
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   5 terms 
  Biochemical function     oxidoreductase activity     6 terms  


DOI no: 10.1126/science.277.5323.202 Science 277:202-206 (1997)
PubMed id: 9211842  
Orbital steering in the catalytic power of enzymes: small structural changes with large catalytic consequences.
A.D.Mesecar, B.L.Stoddard, D.E.Koshland.
Small structural perturbations in the enzyme isocitrate dehydrogenase (IDH) were made in order to evaluate the contribution of precise substrate alignment to the catalytic power of an enzyme. The reaction trajectory of IDH was modified (i) after the adenine moiety of nicotinamide adenine dinucleotide phosphate was changed to hypoxanthine (the 6-amino was changed to 6-hydroxyl), and (ii) by replacing Mg2+, which has six coordinating ligands, with Ca2+, which has eight coordinating ligands. Both changes make large (10(-3) to 10(-5)) changes in the reaction velocity but only small changes in the orientation of the substrates (both distance and angle) as revealed by cryocrystallographic trapping of active IDH complexes. The results provide evidence that orbital overlap produced by optimal orientation of reacting orbitals plays a major quantitative role in the catalytic power of enzymes.
  Selected figure(s)  
Figure 1.
Fig. 1. Orbital steering in enzyme-catalyzed reactions can lead (A) to properly aligned substrates by maximizing bonding orbital overlaps and minimizing anti-bonding orbital overlaps or can lead^ (B) to improperly aligned substrates if the reaction coordinate^ trajectory is perturbed by modification.
Figure 2.
Fig. 2. Schematic illustration of NADP and NHDP.
  The above figures are reprinted by permission from the AAAs: Science (1997, 277, 202-206) copyright 1997.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
20069373 J.D.Pollack, X.Pan, and D.K.Pearl (2010).
Concentration of specific amino acids at the catalytic/active centers of highly-conserved "housekeeping" enzymes of central metabolism in archaea, bacteria and Eukaryota: is there a widely conserved chemical signal of prebiotic assembly?
  Orig Life Evol Biosph, 40, 273-302.  
20072606 M.Röttig, C.Rausch, and O.Kohlbacher (2010).
Combining structure and sequence information allows automated prediction of substrate specificities within enzyme families.
  PLoS Comput Biol, 6, e1000636.  
18977360 V.C.Sershon, B.D.Santarsiero, and A.D.Mesecar (2009).
Kinetic and X-ray structural evidence for negative cooperativity in substrate binding to nicotinate mononucleotide adenylyltransferase (NMAT) from Bacillus anthracis.
  J Mol Biol, 385, 867-888.
PDB codes: 2qtm 2qtn 2qtr
18574141 A.D.Mesecar, and K.Ratia (2008).
Viral destruction of cell surface receptors.
  Proc Natl Acad Sci U S A, 105, 8807-8808.  
17634983 K.Imada, T.Tamura, R.Takenaka, I.Kobayashi, K.Namba, and K.Inagaki (2008).
Structure and quantum chemical analysis of NAD+-dependent isocitrate dehydrogenase: hydride transfer and co-factor specificity.
  Proteins, 70, 63-71.
PDB code: 2d4v
18801331 K.McAdams, E.S.Casper, R.Matthew Haas, B.D.Santarsiero, A.L.Eggler, A.Mesecar, and C.J.Halkides (2008).
The structures of T87I phosphono-CheY and T87I/Y106W phosphono-CheY help to explain their binding affinities to the FliM and CheZ peptides.
  Arch Biochem Biophys, 479, 105-113.
PDB codes: 2id7 2id9 2idm
17157318 Y.Wang, and H.C.Guo (2007).
Crystallographic snapshot of a productive glycosylasparaginase-substrate complex.
  J Mol Biol, 366, 82-92.
PDB code: 2gl9
16415859 B.P.English, W.Min, A.M.van Oijen, K.T.Lee, G.Luo, H.Sun, B.J.Cherayil, S.C.Kou, and X.S.Xie (2006).
Ever-fluctuating single enzyme molecules: Michaelis-Menten equation revisited.
  Nat Chem Biol, 2, 87-94.  
16581910 K.Ratia, K.S.Saikatendu, B.D.Santarsiero, N.Barretto, S.C.Baker, R.C.Stevens, and A.D.Mesecar (2006).
Severe acute respiratory syndrome coronavirus papain-like protease: structure of a viral deubiquitinating enzyme.
  Proc Natl Acad Sci U S A, 103, 5717-5722.
PDB code: 2fe8
16672595 R.H.White (2006).
The difficult road from sequence to function.
  J Bacteriol, 188, 3431-3432.  
15937173 E.Frirdich, and C.Whitfield (2005).
Characterization of Gla(KP), a UDP-galacturonic acid C4-epimerase from Klebsiella pneumoniae with extended substrate specificity.
  J Bacteriol, 187, 4104-4115.  
15929998 J.F.Couture, Jésus-Tran, A.M.Roy, L.Cantin, P.L.Côté, P.Legrand, V.Luu-The, F.Labrie, and R.Breton (2005).
Comparison of crystal structures of human type 3 3alpha-hydroxysteroid dehydrogenase reveals an "induced-fit" mechanism and a conserved basic motif involved in the binding of androgen.
  Protein Sci, 14, 1485-1497.
PDB code: 1xjb
15866000 K.L.Morley, and R.J.Kazlauskas (2005).
Improving enzyme properties: when are closer mutations better?
  Trends Biotechnol, 23, 231-237.  
14978299 A.Azzi, S.A.Clark, W.R.Ellington, and M.S.Chapman (2004).
The role of phosphagen specificity loops in arginine kinase.
  Protein Sci, 13, 575-585.
PDB code: 1rl9
11863453 M.Boudvillain, A.Schwartz, and A.R.Rahmouni (2002).
Limited topological alteration of the T7 RNA polymerase active center at intrinsic termination sites.
  Biochemistry, 41, 3137-3146.  
12454458 M.S.Yousef, F.Fabiola, J.L.Gattis, T.Somasundaram, and M.S.Chapman (2002).
Refinement of the arginine kinase transition-state analogue complex at 1.2 A resolution: mechanistic insights.
  Acta Crystallogr D Biol Crystallogr, 58, 2009-2017.
PDB code: 1m15
11284694 B.A.Palfey, O.Björnberg, and K.F.Jensen (2001).
Insight into the chemistry of flavin reduction and oxidation in Escherichia coli dihydroorotate dehydrogenase obtained by rapid reaction studies.
  Biochemistry, 40, 4381-4390.  
11248042 P.Heikinheimo, V.Tuominen, A.K.Ahonen, A.Teplyakov, B.S.Cooperman, A.A.Baykov, R.Lahti, and A.Goldman (2001).
Toward a quantum-mechanical description of metal-assisted phosphoryl transfer in pyrophosphatase.
  Proc Natl Acad Sci U S A, 98, 3121-3126.
PDB codes: 1e6a 1e9g
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
10737790 C.Jelsch, M.M.Teeter, V.Lamzin, V.Pichon-Pesme, R.H.Blessing, and C.Lecomte (2000).
Accurate protein crystallography at ultra-high resolution: valence electron distribution in crambin.
  Proc Natl Acad Sci U S A, 97, 3171-3176.
PDB code: 1ejg
11114510 H.Erlandsen, E.E.Abola, and R.C.Stevens (2000).
Combining structural genomics and enzymology: completing the picture in metabolic pathways and enzyme active sites.
  Curr Opin Struct Biol, 10, 719-730.  
10625484 H.Ma, K.Ratnam, and T.M.Penning (2000).
Mutation of nicotinamide pocket residues in rat liver 3 alpha-hydroxysteroid dehydrogenase reveals different modes of cofactor binding.
  Biochemistry, 39, 102-109.  
10841545 K.S.Kim, K.S.Oh, and J.Y.Lee (2000).
Catalytic role of enzymes: short strong H-bond-induced partial proton shuttles and charge redistributions.
  Proc Natl Acad Sci U S A, 97, 6373-6378.  
10819972 M.B.Murataliev, and R.Feyereisen (2000).
Interaction of NADP(H) with oxidized and reduced P450 reductase during catalysis. Studies with nucleotide analogues.
  Biochemistry, 39, 5066-5074.  
11087384 S.A.Doyle, S.Y.Fung, and D.E.Koshland (2000).
Redesigning the substrate specificity of an enzyme: isocitrate dehydrogenase.
  Biochemistry, 39, 14348-14355.  
11070076 S.Umhau, L.Pollegioni, G.Molla, K.Diederichs, W.Welte, M.S.Pilone, and S.Ghisla (2000).
The x-ray structure of D-amino acid oxidase at very high resolution identifies the chemical mechanism of flavin-dependent substrate dehydrogenation.
  Proc Natl Acad Sci U S A, 97, 12463-12468.
PDB codes: 1c0k 1c0l 1c0p
10381408 A.Kohen, and J.P.Klinman (1999).
Hydrogen tunneling in biology.
  Chem Biol, 6, R191-R198.  
10600126 M.Ortiz-Maldonado, D.Gatti, D.P.Ballou, and V.Massey (1999).
Structure-function correlations of the reaction of reduced nicotinamide analogues with p-hydroxybenzoate hydroxylase substituted with a series of 8-substituted flavins.
  Biochemistry, 38, 16636-16647.
PDB code: 1d7l
10490104 Q.Xu, D.Buckley, C.Guan, and H.C.Guo (1999).
Structural insights into the mechanism of intramolecular proteolysis.
  Cell, 98, 651-661.
PDB codes: 9gaa 9gac 9gaf
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.  
9585527 D.D.Axe, N.W.Foster, and A.R.Fersht (1998).
A search for single substitutions that eliminate enzymatic function in a bacterial ribonuclease.
  Biochemistry, 37, 7157-7166.  
9771734 D.E.Koshland (1998).
Conformational changes: how small is big enough?
  Nat Med, 4, 1112-1114.  
9572848 G.P.Miller, and S.J.Benkovic (1998).
Strength of an interloop hydrogen bond determines the kinetic pathway in catalysis by Escherichia coli dihydrofolate reductase.
  Biochemistry, 37, 6336-6342.  
9671698 G.Zhou, T.Somasundaram, E.Blanc, G.Parthasarathy, W.R.Ellington, and M.S.Chapman (1998).
Transition state structure of arginine kinase: implications for catalysis of bimolecular reactions.
  Proc Natl Acad Sci U S A, 95, 8449-8454.
PDB code: 1bg0
9871671 K.H.Glüsenkamp, C.Mengede, W.Drosdziok, E.Jähde, and M.F.Rajewsky (1998).
Rapid hydrolysis of amides under physiological conditions: influence of the microenvironment on the stability of the amide bond.
  Bioorg Med Chem Lett, 8, 285-288.  
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
9707558 K.P.Hopfner, E.Kopetzki, G.B.Kresse, W.Bode, R.Huber, and R.A.Engh (1998).
New enzyme lineages by subdomain shuffling.
  Proc Natl Acad Sci U S A, 95, 9813-9818.
PDB code: 1fxy
9519410 M.S.Jurica, A.Mesecar, P.J.Heath, W.Shi, T.Nowak, and B.L.Stoddard (1998).
The allosteric regulation of pyruvate kinase by fructose-1,6-bisphosphate.
  Structure, 6, 195-210.
PDB codes: 1a3w 1a3x
9724533 P.H.Liang, and K.S.Anderson (1998).
Substrate channeling and domain-domain interactions in bifunctional thymidylate synthase-dihydrofolate reductase.
  Biochemistry, 37, 12195-12205.  
9434899 A.Mattevi, M.A.Vanoni, and B.Curti (1997).
Structure of D-amino acid oxidase: new insights from an old enzyme.
  Curr Opin Struct Biol, 7, 804-810.  
9345628 K.Moffat, and Z.Ren (1997).
Synchrotron radiation applications to macromolecular crystallography.
  Curr Opin Struct Biol, 7, 689-696.  
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.