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Immunoglobulin PDB id
1a3l
Jmol
Contents
Protein chains
217 a.a. *
218 a.a. *
Ligands
CFC
Waters ×309
* Residue conservation analysis
PDB id:
1a3l
Name: Immunoglobulin
Title: Catalysis of a disfavored reaction: an antibody exo diels- alderase-tsa-inhibitor complex at 1.95 a resolution
Structure: Immunoglobulin fab 13g5 (light chain). Chain: l. Fragment: immunoglobulin fab fragment. Immunoglobulin fab 13g5 (heavy chain). Chain: h. Fragment: immunoglobulin fab fragment
Source: Mus musculus. House mouse. Organism_taxid: 10090. Cell_line: 13g5 murine hybridoma. Cell_line: 13g5 murine hybridoma
Biol. unit: Dimer (from PQS)
Resolution:
1.95Å     R-factor:   0.188     R-free:   0.265
Authors: A.Heine,I.A.Wilson
Key ref:
A.Heine et al. (1998). An antibody exo Diels-Alderase inhibitor complex at 1.95 angstrom resolution. Science, 279, 1934-1940. PubMed id: 9506943 DOI: 10.1126/science.279.5358.1934
Date:
22-Jan-98     Release date:   16-Feb-99    
PROCHECK
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 Headers
 References

 

 
DOI no: 10.1126/science.279.5358.1934 Science 279:1934-1940 (1998)
PubMed id: 9506943  
 
 
An antibody exo Diels-Alderase inhibitor complex at 1.95 angstrom resolution.
A.Heine, E.A.Stura, J.T.Yli-Kauhaluoma, C.Gao, Q.Deng, B.R.Beno, K.N.Houk, K.D.Janda, I.A.Wilson.
 
  ABSTRACT  
 
A highly specific Diels-Alder protein catalyst was made by manipulating the antibody repertoire of the immune system. The catalytic antibody 13G5 catalyzes a disfavored exo Diels-Alder transformation in a reaction for which there is no natural enzyme counterpart and that yields a single regioisomer in high enantiomeric excess. The crystal structure of the antibody Fab in complex with a ferrocenyl inhibitor containing the essential haptenic core that elicited 13G5 was determined at 1.95 angstrom resolution. Three key antibody residues appear to be responsible for the observed catalysis and product control. Tyrosine-L36 acts as a Lewis acid activating the dienophile for nucleophilic attack, and asparagine-L91 and aspartic acid-H50 form hydrogen bonds to the carboxylate side chain that substitutes for the carbamate diene substrate. This hydrogen-bonding scheme leads to rate acceleration and also pronounced stereoselectivity. Docking experiments with the four possible ortho transition states of the reaction explain the specific exo effect and suggest that the (3R,4R)-exo stereoisomer is the preferred product.
 
  Selected figure(s)  
 
Figure 4.
Fig. 4. Specific interactions of 9 with side chains of the Fab 13G5 in the antibody-antigen complex. Three hydrogen bonds are formed with Fab residues TyrL36, AspH50, and AsnL91. In addition, a water molecule O87 is in close contact to ferrocene 9. The hydrogen-bonding network in the Fab combining site that orients the side chains of TyrL36, AspH50, and AsnL91 in position to form hydrogen bonds with 9 are shown in (B). For AsnL91, this network is extended over three residues. Oxygen atoms are^ shown in red and nitrogen atoms in blue. Figures 4 and 5 were^ produced with XP (31). 		Figure 8.
Fig. 8. Favored orientations for each of the four isomeric transition states in antibody 13G5 predicted by AUTODOCK: (A) (3R,4R)-exo, (B) (3S,4S)-exo, (C) (3R,4S)-endo, and (D) (3S,4R)-endo. The lowest energy structures in (A), (C), and (D), and the second lowest in (B) are shown. Only the transition states of the reaction (Fig. 1) and the interacting side chains that form hydrogen bonds in the crystal structure of the ferrocenyl inhibitor are shown for clarity. Only in the exo forms are all three hydrogen bonds made that are observed in the crystal structure^ of the inhibitor-Fab complex.
 
  The above figures are reprinted by permission from the AAAs: Science (1998, 279, 1934-1940) copyright 1998.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
19304744 K.T.Gagnon, S.Y.Ju, M.B.Goshe, E.S.Maxwell, and S.Franzen (2009).
A role for hydrophobicity in a Diels-Alder reaction catalyzed by pyridyl-modified RNA.
  Nucleic Acids Res, 37, 3074-3082.  
19154113 Y.H.Lam, P.H.Cheong, J.M.Blasco Mata, S.J.Stanway, V.Gouverneur, and K.N.Houk (2009).
Diels-Alder exo selectivity in terminal-substituted dienes and dienophiles: experimental discoveries and computational explanations.
  J Am Chem Soc, 131, 1947-1957.  
17876816 B.Fischer, K.Fukuzawa, and W.Wenzel (2008).
Receptor-specific scoring functions derived from quantum chemical models improve affinity estimates for in-silico drug discovery.
  Proteins, 70, 1264-1273.  
18172831 D.I.Ranieri, D.M.Corgliano, E.J.Franco, H.Hofstetter, and O.Hofstetter (2008).
Investigation of the stereoselectivity of an anti-amino acid antibody using molecular modeling and ligand docking.
  Chirality, 20, 559-570.  
17427957 B.Fischer, S.Basili, H.Merlitz, and W.Wenzel (2007).
Accuracy of binding mode prediction with a cascadic stochastic tunneling method.
  Proteins, 68, 195-204.  
17400249 E.W.Debler, G.F.Kaufmann, R.N.Kirchdoerfer, J.M.Mee, K.D.Janda, and I.A.Wilson (2007).
Crystal structures of a quorum-quenching antibody.
  J Mol Biol, 368, 1392-1402.
PDB codes: 2ntf 2op4
16721886 L.Barisić, M.Cakić, K.A.Mahmoud, Y.N.Liu, H.B.Kraatz, H.Pritzkow, S.I.Kirin, N.Metzler-Nolte, and V.Rapić (2006).
Helically chiral ferrocene peptides containing 1'-aminoferrocene-1-carboxylic acid subunits as turn inducers.
  Chemistry, 12, 4965-4980.  
16491487 M.S.Taylor, and E.N.Jacobsen (2006).
Asymmetric catalysis by chiral hydrogen-bond donors.
  Angew Chem Int Ed Engl, 45, 1520-1543.  
16528766 M.T.Reetz, and N.Jiao (2006).
Copper-phthalocyanine conjugates of serum albumins as enantioselective catalysts in Diels-Alder reactions.
  Angew Chem Int Ed Engl, 45, 2416-2419.  
15723077 A.Serganov, S.Keiper, L.Malinina, V.Tereshko, E.Skripkin, C.Höbartner, A.Polonskaia, A.T.Phan, R.Wombacher, R.Micura, Z.Dauter, A.Jäschke, and D.J.Patel (2005).
Structural basis for Diels-Alder ribozyme-catalyzed carbon-carbon bond formation.
  Nat Struct Mol Biol, 12, 218-224.
PDB codes: 1ykq 1ykv 1yls
16260754 J.J.Agresti, B.T.Kelly, A.Jäschke, and A.D.Griffiths (2005).
Selection of ribozymes that catalyse multiple-turnover Diels-Alder cycloadditions by using in vitro compartmentalization.
  Proc Natl Acad Sci U S A, 102, 16170-16175.  
15670909 L.Zheng, R.Manetsch, W.D.Woggon, U.Baumann, and J.L.Reymond (2005).
Mechanistic study of proton transfer and hysteresis in catalytic antibody 16E7 by site-directed mutagenesis and homology modeling.
  Bioorg Med Chem, 13, 1021-1029.  
16003810 V.Gouverneur, and M.Reiter (2005).
Biocatalytic approaches to hetero-Diels-Alder adducts of carbonyl compounds.
  Chemistry, 11, 5806-5815.  
14982995 X.Zhu, P.Wentworth, A.D.Wentworth, A.Eschenmoser, R.A.Lerner, and I.A.Wilson (2004).
Probing the antibody-catalyzed water-oxidation pathway at atomic resolution.
  Proc Natl Acad Sci U S A, 101, 2247-2252.
PDB codes: 1ru9 1rua 1ruk 1rul 1rum 1rup 1ruq 1rur
12634789 T.Ose, K.Watanabe, T.Mie, M.Honma, H.Watanabe, M.Yao, H.Oikawa, and I.Tanaka (2003).
Insight into a natural Diels-Alder reaction from the structure of macrophomate synthase.
  Nature, 422, 185-189.
PDB code: 1izc
12093912 M.Hugot, N.Bensel, M.Vogel, M.T.Reymond, B.Stadler, J.L.Reymond, and U.Baumann (2002).
A structural basis for the activity of retro-Diels-Alder catalytic antibodies: evidence for a catalytic aromatic residue.
  Proc Natl Acad Sci U S A, 99, 9674-9678.
PDB codes: 1lo0 1lo2 1lo3 1lo4
12045324 R.M.Williams (2002).
Total synthesis and biosynthesis of the paraherquamides: an intriguing story of the biological Diels-Alder construction.
  Chem Pharm Bull (Tokyo), 50, 711-740.  
11688715 A.Jäschke (2001).
RNA-catalyzed carbon-carbon bond formation.
  Biol Chem, 382, 1321-1325.  
  11410373 D.J.Tantillo, and K.N.Houk (2001).
Canonical binding arrays as molecular recognition elements in the immune system: tetrahedral anions and the ester hydrolysis transition state.
  Chem Biol, 8, 535-545.  
11948875 G.Pohnert (2001).
Diels-Alderases.
  Chembiochem, 2, 873-875.  
10963661 B.Golinelli-Pimpaneau, O.Goncalves, T.Dintinger, D.Blanchard, M.Knossow, and C.Tellier (2000).
Structural evidence for a programmed general base in the active site of a catalytic antibody.
  Proc Natl Acad Sci U S A, 97, 9892-9895.
PDB code: 1f3d
11114507 B.Golinelli-Pimpaneau (2000).
Novel reactions catalysed by antibodies.
  Curr Opin Struct Biol, 10, 697-708.  
11828417 J.Chen, Q.Deng, R.Wang, K.Houk, and D.Hilvert (2000).
Shape complementarity, binding-site dynamics, and transition state stabilization: a theoretical study of Diels-Alder catalysis by antibody 1E9.
  Chembiochem, 1, 255-261.  
10585916 W.Radding, T.Romo, and G.N.Phillips (1999).
Protein-assisted pericyclic reactions: an alternate hypothesis for the action of quantal receptors.
  Biophys J, 77, 2920-2929.  
  9914196 D.J.Tantillo, J.Chen, and K.N.Houk (1998).
Theozymes and compuzymes: theoretical models for biological catalysis.
  Curr Opin Chem Biol, 2, 743-750.  
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.