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PDBsum entry 1axt
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Immunoglobulin PDB id
1axt

 

 

 

 

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Contents
Protein chains
216 a.a. *
218 a.a. *
Waters ×248
* Residue conservation analysis
PDB id:
1axt
Name: Immunoglobulin
Title: Immune versus natural selection: antibody aldolases with the rates of natural enzymes
Structure: Immunoglobulin igg2a. Chain: l. Fragment: fab' fragment 33f12. Immunoglobulin igg2a. Chain: h. Fragment: fab' fragment 33f12
Source: Mus musculus. House mouse. Organism_taxid: 10090. Strain: balb/c. Other_details: monoclonal antibody igg2a fab' fragment. Other_details: monoclonal antibody igg2a fab' fragment
Biol. unit: Dimer (from PQS)
Resolution:
2.15Å     R-factor:   0.214     R-free:   0.317
Authors: A.Heine,I.A.Wilson
Key ref:
C.F.Barbas et al. (1997). Immune versus natural selection: antibody aldolases with enzymic rates but broader scope. Science, 278, 2085-2092. PubMed id: 9405338 DOI: 10.1126/science.278.5346.2085
Date:
20-Oct-97     Release date:   28-Oct-98    
PROCHECK
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 Headers
 References

Protein chain
No UniProt id for this chain
Struc: 216 a.a.
Protein chain
Pfam   ArchSchema ?
P01865  (GCAM_MOUSE) -  Immunoglobulin heavy constant gamma 2A from Mus musculus
Seq:
Struc: 		398 a.a.
218 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 

 
DOI no: 10.1126/science.278.5346.2085 Science 278:2085-2092 (1997)
PubMed id: 9405338  
 
 
Immune versus natural selection: antibody aldolases with enzymic rates but broader scope.
C.F.Barbas, A.Heine, G.Zhong, T.Hoffmann, S.Gramatikova, R.Björnestedt, B.List, J.Anderson, E.A.Stura, I.A.Wilson, R.A.Lerner.
 
  ABSTRACT  
 
Structural and mechanistic studies show that when the selection criteria of the immune system are changed, catalytic antibodies that have the efficiency of natural enzymes evolve, but the catalytic antibodies are much more accepting of a wide range of substrates. The catalytic antibodies were prepared by reactive immunization, a process whereby the selection criteria of the immune system are changed from simple binding to chemical reactivity. This process yielded aldolase catalytic antibodies that approximated the rate acceleration of the natural enzyme used in glycolysis. Unlike the natural enzyme, however, the antibody aldolases catalyzed a variety of aldol reactions and decarboxylations. The crystal structure of one of these antibodies identified the reactive lysine residue that was selected in the immunization process. This lysine is deeply buried in a hydrophobic pocket at the base of the binding site, thereby accounting for its perturbed pKa.
 
  Selected figure(s)  
 
Figure 2.
Fig. 2. Comparison of the optimal reactions catalyzed by FDP aldolase class I and the antibody aldolases. R = 4-isobutyramidobenzyl or n-butyl. 		Figure 7.
Fig. 7. Comparison of two antibody-combining sites that contain LysH93. The environment of LysH93 is very hydrophobic in antibody Fab 33F12 (A) compared^ to antibody Fab 17E8 (27) (PDB code 1eap) (B). Residues in an 8 Å sphere around LysH93N are shown. A space-filling CPK representation of the environment around LysH93 is shown with hydrophobic atoms in yellow, and polar nitrogen and oxygen atoms in cyan and salmon, respectively. Charged basic^ residues have their nitrogen atoms colored dark blue and charged^ oxygen atoms are colored in red. The LysH93N atom is colored in blue.
 
  The above figures are reprinted by permission from the AAAs: Science (1997, 278, 2085-2092) copyright 1997.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
21359299 A.Kumar, S.Singh, V.Kumar, and S.S.Chimni (2011).
Asymmetric syn-selective direct aldol reaction of protected hydroxyacetone catalyzed by primary amino acid derived bifunctional organocatalyst in the presence of water.
  Org Biomol Chem, 9, 2731-2742.  
20845359 J.Gavrilyuk, H.Uehara, N.Otsubo, A.Hessell, D.R.Burton, and C.F.Barbas (2010).
Potent inhibition of HIV-1 entry with a chemically programmed antibody aided by an efficient organocatalytic synthesis.
  Chembiochem, 11, 2113-2118.  
20194782 J.K.Lassila, D.Baker, and D.Herschlag (2010).
Origins of catalysis by computationally designed retroaldolase enzymes.
  Proc Natl Acad Sci U S A, 107, 4937-4942.  
20617260 N.Mase, and C.F.Barbas (2010).
In water, on water, and by water: mimicking nature's aldolases with organocatalysis and water.
  Org Biomol Chem, 8, 4043-4050.  
21149738 V.R.Doppalapudi, J.Huang, D.Liu, P.Jin, B.Liu, L.Li, J.Desharnais, C.Hagen, N.J.Levin, M.J.Shields, M.Parish, R.E.Murphy, J.Del Rosario, B.D.Oates, J.Y.Lai, M.J.Matin, Z.Ainekulu, A.Bhat, C.W.Bradshaw, G.Woodnutt, R.A.Lerner, and R.W.Lappe (2010).
Chemical generation of bispecific antibodies.
  Proc Natl Acad Sci U S A, 107, 22611-22616.  
20694218 X.H.Chen, J.Yu, and L.Z.Gong (2010).
The role of double hydrogen bonds in asymmetric direct aldol reactions catalyzed by amino amide derivatives.
  Chem Commun (Camb), 46, 6437-6448.  
19173313 D.C.de Geus, A.M.van Roon, E.A.Thomassen, C.H.Hokke, A.M.Deelder, and J.P.Abrahams (2009).
Characterization of a diagnostic Fab fragment binding trimeric Lewis X.
  Proteins, 76, 439-447.
PDB code: 2vq1
19181522 J.I.Gavrilyuk, U.Wuellner, and C.F.Barbas (2009).
Beta-lactam-based approach for the chemical programming of aldolase antibody 38C2.
  Bioorg Med Chem Lett, 19, 1421-1424.  
19497743 J.I.Gavrilyuk, U.Wuellner, S.Salahuddin, R.K.Goswami, S.C.Sinha, and C.F.Barbas (2009).
An efficient chemical approach to bispecific antibodies and antibodies of high valency.
  Bioorg Med Chem Lett, 19, 3716-3720.  
19759009 L.Holm, P.Moody, and M.Howarth (2009).
Electrophilic affibodies forming covalent bonds to protein targets.
  J Biol Chem, 284, 32906-32913.  
19458715 M.C.Ho, J.F.Ménétret, H.Tsuruta, and K.N.Allen (2009).
The origin of the electrostatic perturbation in acetoacetate decarboxylase.
  Nature, 459, 393-397.
PDB codes: 3bgt 3bh2 3bh3
19428247 R.K.Goswami, Z.Z.Huang, J.S.Forsyth, B.Felding-Habermann, and S.C.Sinha (2009).
Multiple catalytic aldolase antibodies suitable for chemical programming.
  Bioorg Med Chem Lett, 19, 3821-3824.  
19746465 S.Itoh, M.Kitamura, Y.Yamada, and S.Aoki (2009).
Chiral catalysts dually functionalized with amino acid and Zn2+ complex components for enantioselective direct aldol reactions inspired by natural aldolases: design, synthesis, complexation properties, catalytic activities, and mechanistic study.
  Chemistry, 15, 10570-10584.  
21581697 C.Y.Wang (2008).
(E)-N-(2,3,4-Trimeth-oxy-6-methyl-benzyl-idene)naphthalen-1-amine.
  Acta Crystallogr Sect E Struct Rep Online, 65, o56.  
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
17653365 S.Sulzer-Mossé, and A.Alexakis (2007).
Chiral amines as organocatalysts for asymmetric conjugate addition to nitroolefins and vinyl sulfones via enamine activation.
  Chem Commun (Camb), (), 3123-3135.  
21200932 Y.W.Wang, and Y.Peng (2007).
(S)-2-(Iodo-meth-yl)-1-tosyl-pyrrolidine.
  Acta Crystallogr Sect E Struct Rep Online, 64, o56.  
16822849 F.Guo, S.Das, B.M.Mueller, C.F.Barbas, R.A.Lerner, and S.C.Sinha (2006).
Breaking the one antibody-one target axiom.
  Proc Natl Acad Sci U S A, 103, 11009-11014.  
16787052 G.Gao, R.Prasad, S.N.Lodwig, C.J.Unkefer, W.A.Beard, S.H.Wilson, and R.E.London (2006).
Determination of lysine pK values using [5-13C]lysine: application to the lyase domain of DNA Pol beta.
  J Am Chem Soc, 128, 8104-8105.  
16575434 J.Kofoed, T.Darbre, and J.L.Reymond (2006).
Dual mechanism of zinc-proline catalyzed aldol reactions in water.
  Chem Commun (Camb), (), 1482-1484.  
16502453 J.M.Notestein, and A.Katz (2006).
Enhancing heterogeneous catalysis through cooperative hybrid organic-inorganic interfaces.
  Chemistry, 12, 3954-3965.  
17120282 R.A.Lerner (2006).
Manufacturing immunity to disease in a test tube: the magic bullet realized.
  Angew Chem Int Ed Engl, 45, 8106-8125.  
16211623 F.Tanaka (2005).
Development of protein, peptide, and small molecule catalysts using catalysis-based selection strategies.
  Chem Rec, 5, 276-285.  
16003810 V.Gouverneur, and M.Reiter (2005).
Biocatalytic approaches to hetero-Diels-Alder adducts of carbonyl compounds.
  Chemistry, 11, 5806-5815.  
14993682 B.Liotard, and J.Sygusch (2004).
Purification, crystallization and preliminary X-ray analysis of native and selenomethionine class I tagatose-1,6-bisphosphate aldolase from Streptococcus pyogenes.
  Acta Crystallogr D Biol Crystallogr, 60, 528-530.  
15073330 B.List, L.Hoang, and H.J.Martin (2004).
New mechanistic studies on the proline-catalyzed aldol reaction.
  Proc Natl Acad Sci U S A, 101, 5839-5842.  
15388865 J.Warwicker (2004).
Improved pKa calculations through flexibility based sampling of a water-dominated interaction scheme.
  Protein Sci, 13, 2793-2805.  
14981258 S.C.Sinha, L.S.Li, G.P.Miller, S.Dutta, C.Rader, and R.A.Lerner (2004).
Prodrugs of dynemicin analogs for selective chemotherapy mediated by an aldolase catalytic Ab.
  Proc Natl Acad Sci U S A, 101, 3095-3099.  
15067133 S.E.Denmark, and T.Bui (2004).
Chiral phosphoramide-catalyzed, enantioselective, directed cross-aldol reactions of aldehydes.
  Proc Natl Acad Sci U S A, 101, 5439-5444.  
12702756 C.Rader, S.C.Sinha, M.Popkov, R.A.Lerner, and C.F.Barbas (2003).
Chemically programmed monoclonal antibodies for cancer therapy: adaptor immunotherapy based on a covalent antibody catalyst.
  Proc Natl Acad Sci U S A, 100, 5396-5400.  
14500876 L.C.James, and D.S.Tawfik (2003).
The specificity of cross-reactivity: promiscuous antibody binding involves specific hydrogen bonds rather than nonspecific hydrophobic stickiness.
  Protein Sci, 12, 2183-2193.  
12672110 M.Allert, and L.Baltzer (2003).
Noncovalent binding of a reaction intermediate by a designed helix-loop-helix motif-implications for catalyst design.
  Chembiochem, 4, 306-318.  
11822454 A.Shulman, D.Sitry, H.Shulman, and E.Keinan (2002).
Highly efficient antibody-catalyzed deuteration of carbonyl compounds.
  Chemistry, 8, 229-239.  
11880619 K.M.Nicholas, P.Wentworth, C.W.Harwig, A.D.Wentworth, A.Shafton, and K.D.Janda (2002).
A cofactor approach to copper-dependent catalytic antibodies.
  Proc Natl Acad Sci U S A, 99, 2648-2653.  
12144924 Q.Wang, E.Kaltgrad, T.Lin, J.E.Johnson, and M.G.Finn (2002).
Natural supramolecular building blocks. Wild-type cowpea mosaic virus.
  Chem Biol, 9, 805-811.  
11165171 C.Rader (2001).
Antibody libraries in drug and target discovery.
  Drug Discov Today, 6, 36-43.  
11707596 D.S.Worrall, J.E.McDunn, B.List, D.Reichart, A.Hevener, T.Gustafson, C.F.Barbas, R.A.Lerner, and J.M.Olefsky (2001).
Synthesis of an organoinsulin molecule that can be activated by antibody catalysis.
  Proc Natl Acad Sci U S A, 98, 13514-13518.  
11404472 D.Shabat, H.N.Lode, U.Pertl, R.A.Reisfeld, C.Rader, R.A.Lerner, and C.F.Barbas (2001).
In vivo activity in a catalytic antibody-prodrug system: Antibody catalyzed etoposide prodrug activation for selective chemotherapy.
  Proc Natl Acad Sci U S A, 98, 7528-7533.  
11274385 J.Allard, P.Grochulski, and J.Sygusch (2001).
Covalent intermediate trapped in 2-keto-3-deoxy-6- phosphogluconate (KDPG) aldolase structure at 1.95-A resolution.
  Proc Natl Acad Sci U S A, 98, 3679-3684.
PDB codes: 1eua 1eun
11714928 L.C.James, and D.S.Tawfik (2001).
Catalytic and binding poly-reactivities shared by two unrelated proteins: The potential role of promiscuity in enzyme evolution.
  Protein Sci, 10, 2600-2607.  
11349910 S.C.Sinha, J.Sun, G.P.Miller, M.Wartmann, and R.A.Lerner (2001).
Catalytic antibody route to the naturally occurring epothilones: total synthesis of epothilones A-F.
  Chemistry, 7, 1691-1702.  
11893065 S.Matile (2001).
Bioorganic chemistry à la baguette: studies on molecular recognition in biological systems using rigid-rod molecules.
  Chem Rec, 1, 162-172.  
10975453 A.D.Griffiths, and D.S.Tawfik (2000).
Man-made enzymes--from design to in vitro compartmentalisation.
  Curr Opin Biotechnol, 11, 338-353.  
10760259 A.Karlstrom, G.Zhong, C.Rader, N.A.Larsen, A.Heine, R.Fuller, B.List, F.Tanaka, I.A.Wilson, C.F.Barbas, and R.A.Lerner (2000).
Using antibody catalysis to study the outcome of multiple evolutionary trials of a chemical task.
  Proc Natl Acad Sci U S A, 97, 3878-3883.  
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.  
10966475 D.Hilvert (2000).
Critical analysis of antibody catalysis.
  Annu Rev Biochem, 69, 751-793.  
11128279 R.Pérez Carlón, N.Jourdain, and J.L.Reymond (2000).
Fluorogenic polypropionate fragments for detecting stereoselective aldolases.
  Chemistry, 6, 4154-4162.  
10712619 S.M.Zgiby, G.J.Thomson, S.Qamar, and A.Berry (2000).
Exploring substrate binding and discrimination in fructose1, 6-bisphosphate and tagatose 1,6-bisphosphate aldolases.
  Eur J Biochem, 267, 1858-1868.  
10921867 T.Izard, and N.C.Blackwell (2000).
Crystal structures of the metal-dependent 2-dehydro-3-deoxy-galactarate aldolase suggest a novel reaction mechanism.
  EMBO J, 19, 3849-3856.
PDB codes: 1dxe 1dxf
10611676 A.B.Martin, and P.G.Schultz (1999).
Opportunities at the interface of chemistry and biology.
  Trends Cell Biol, 9, M24-M28.  
10398410 A.Huber, S.Demartis, and D.Neri (1999).
The use of biosensor technology for the engineering of antibodies and enzymes.
  J Mol Recognit, 12, 198-216.  
10574796 B.Gigant, T.Tsumuraya, I.Fujii, and M.Knossow (1999).
Diverse structural solutions to catalysis in a family of antibodies.
  Structure, 7, 1385-1393.
PDB code: 1ct8
10359815 D.Shabat, C.Rader, B.List, R.A.Lerner, and C.F.Barbas (1999).
Multiple event activation of a generic prodrug trigger by antibody catalysis.
  Proc Natl Acad Sci U S A, 96, 6925-6930.  
10476880 F.Grynszpan, and E.Keinan (1999).
Opsin shift in an aldolase antibody.
  Bioorg Med Chem Lett, 9, 2419-2424.  
10322147 M.Wabl, M.Cascalho, and C.Steinberg (1999).
Hypermutation in antibody affinity maturation.
  Curr Opin Immunol, 11, 186-189.  
10393309 N.C.Blackwell, P.M.Cullis, R.A.Cooper, and T.Izard (1999).
Rhombohedral crystals of 2-dehydro-3-deoxygalactarate aldolase from Escherichia coli.
  Acta Crystallogr D Biol Crystallogr, 55, 1368-1369.  
10449375 R.W.Roberts, and W.W.Ja (1999).
In vitro selection of nucleic acids and proteins: What are we learning?
  Curr Opin Struct Biol, 9, 521-529.  
10089402 S.Trakhanov, S.Parkin, R.Raffaï, R.Milne, Y.M.Newhouse, K.H.Weisgraber, and B.Rupp (1999).
Structure of a monoclonal 2E8 Fab antibody fragment specific for the low-density lipoprotein-receptor binding region of apolipoprotein E refined at 1.9 A.
  Acta Crystallogr D Biol Crystallogr, 55, 122-128.
PDB code: 12e8
10214693 B.Avalle, V.Zanin, D.Thomas, and A.Friboulet (1998).
Antibody catalysis based on functional mimicry.
  Appl Biochem Biotechnol, 75, 3.  
9860972 B.List, C.F.Barbas, and R.A.Lerner (1998).
Aldol sensors for the rapid generation of tunable fluorescence by antibody catalysis.
  Proc Natl Acad Sci U S A, 95, 15351-15355.  
9592389 C.F.Barbas, and B.List (1998).
Alchemy, enzymes, and the blind-watchmaker.
  Nat Biotechnol, 16, 423-424.  
9843932 P.G.Schultz (1998).
Bringing biological solutions to chemical problems.
  Proc Natl Acad Sci U S A, 95, 14590-14591.  
9720265 P.J.Hudson (1998).
Recombinant antibody fragments.
  Curr Opin Biotechnol, 9, 395-402.  
9843936 S.C.Sinha, C.F.Barbas, and R.A.Lerner (1998).
The antibody catalysis route to the total synthesis of epothilones.
  Proc Natl Acad Sci U S A, 95, 14603-14608.  
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.

 

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