PDBsum entry 3b5l

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protein ligands links
Hydrolase PDB id
Protein chain
198 a.a. *
SO4 ×2
NH4 ×2
Waters ×174
* Residue conservation analysis
PDB id:
Name: Hydrolase
Title: Crystal structure of a novel engineered retroaldolase: ra-61
Structure: Endoxylanase. Chain: b. Engineered: yes
Source: Artificial gene. Organism_taxid: 32630. Expressed in: escherichia coli. Expression_system_taxid: 562. Other_details: computationally designed based on the struct thermophilic b-1,4-xylanase from nonomuraea flexuosa
1.80Å     R-factor:   0.206     R-free:   0.248
Authors: B.L.Stoddard,L.A.Doyle
Key ref:
L.Jiang et al. (2008). De novo computational design of retro-aldol enzymes. Science, 319, 1387-1391. PubMed id: 18323453 DOI: 10.1126/science.1152692
26-Oct-07     Release date:   22-Jan-08    
Go to PROCHECK summary

Protein chain
Pfam   ArchSchema ?
Q8GMV7  (Q8GMV7_9ACTO) -  Endo-1,4-beta-xylanase
344 a.a.
198 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 11 residue positions (black crosses)

 Enzyme reactions 
   Enzyme class: E.C.  - Endo-1,4-beta-xylanase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: Endohydrolysis of 1,4-beta-D-xylosidic linkages in xylans.
 Gene Ontology (GO) functional annotation 
  GO annot!
  Biological process     carbohydrate metabolic process   1 term 
  Biochemical function     hydrolase activity, hydrolyzing O-glycosyl compounds     1 term  


DOI no: 10.1126/science.1152692 Science 319:1387-1391 (2008)
PubMed id: 18323453  
De novo computational design of retro-aldol enzymes.
L.Jiang, E.A.Althoff, F.R.Clemente, L.Doyle, D.Röthlisberger, A.Zanghellini, J.L.Gallaher, J.L.Betker, F.Tanaka, C.F.Barbas, D.Hilvert, K.N.Houk, B.L.Stoddard, D.Baker.
The creation of enzymes capable of catalyzing any desired chemical reaction is a grand challenge for computational protein design. Using new algorithms that rely on hashing techniques to construct active sites for multistep reactions, we designed retro-aldolases that use four different catalytic motifs to catalyze the breaking of a carbon-carbon bond in a nonnatural substrate. Of the 72 designs that were experimentally characterized, 32, spanning a range of protein folds, had detectable retro-aldolase activity. Designs that used an explicit water molecule to mediate proton shuffling were significantly more successful, with rate accelerations of up to four orders of magnitude and multiple turnovers, than those involving charged side-chain networks. The atomic accuracy of the design process was confirmed by the x-ray crystal structure of active designs embedded in two protein scaffolds, both of which were nearly superimposable on the design model.
  Selected figure(s)  
Figure 2.
Fig. 2. Retro-aldol reaction and active-site motifs. (A) The retro-aldol reaction. (B) General description of the aldol reaction pathway with a nucleophilic lysine and general acid-base chemistry. Several of the proton transfer steps are left out for brevity. (C) Active-site motifs with quantum mechanically optimized structures (23). (Top left) Motif I. Two lysines are positioned nearby one another to lower the pK[a] of the nucleophilic lysine, and a Lys-Asp dyad acts as the base to deprotonate the hydroxyl group. (Bottom left) Motif II. The catalytic lysine is buried in a hydrophobic environment to lower its pK[a] to make it a more potent nucleophile, and a tyrosine functions as a general acid or base. HB, hydrogen-bond. (Top right) Motif III. The catalytic lysine, analogous to motif II, is placed in a hydrophobic pocket to alter its pK[a], and a His-Asp dyad serves as a general base similar to the catalytic unit commonly observed in the serine proteases (24). (Bottom right) Motif IV. The catalytic lysine is again positioned in a hydrophobic environment. Additionally, an explicitly modeled bound water molecule is placed such that it forms a hydrogen bond with the carbinolamine hydroxyl during its formation, aids in the water elimination step, and deprotonates the β-alcohol at the carbon-carbon bond–breaking step. A hydrogen-bond donor/acceptor, such as Ser, Thr, or Tyr, is placed to position the water molecule in a tetrahedral geometry with the β-alcohol and the carbinolamine hydroxyl. The proton-abstracting ability of the water molecule is enhanced by a second hydrogen bond with a base residue. We incorporated, where possible, additional hydrogen-bonding interactions to stabilize the carbinolamine hydroxyl group and an aromatic side chain to optimally pack along the planar aromatic moiety of the substrate.
Figure 4.
Fig. 4. Structures of designed enzymes. (A to C) Examples of designmodels for active designs highlighting groups important for catalysis. The nucleophilic imine-forming lysine is in orange, the TS model is in yellow, the hydrogen-bonding groups are in light green, and the catalytic water is shown explicitly. The designed hydrophobic binding site for the aromatic portion of the TS model is indicated by the gray mesh. (A) RA60 (catalytic motif IV, jelly-roll scaffold). A designed hydrophobic pocket encloses the aromatic portion of the substrate and packs the aliphatic portion of the imine-forming Lys^48. A designed hydrogen-bonding network positions the bridging water molecule and the composite TS. (B) RA46 (catalytic motif IV, TIM-barrel scaffold). Tyr^83 and Ser^210 position the bridging water molecule, which facilitates the proton shuffling required in active site IV. (C) RA45 (catalytic motif IV, TIM-barrel scaffold). The bridging water is hydrogen-bonded by Ser^211 and Glu^233; replacing the Glu^233 with Thr decreases catalytic activity threefold (Fig. 3A). (D and E) Overlay of design model (purple) on x-ray crystal structure (green). Designed amino acid side chains are shown in stick representation, and the TS model in the design is shown in gray. (D) The 2.2 Å crystal structure of the S210A variant of RA22 (catalytic motif III, TIM-barrel scaffold). The C root mean square deviation (RMSD) between the design model and crystal structure is 0.62 Å, and the heavy-atom RMSD in the active site is 1.10 Å. (E) 1.8 Å crystal structure of M48K variant of RA61 (catalytic motif IV, jelly-roll scaffold). Design-crystal structure C RMSD is 0.46 Å, and heavy-atom RMSD is 0.8 Å. The small differences in the high-resolution details of packing around the active site are due to slight movements in some of the loops above the binding pocket and two rotamer changes in RA61 that may reflect the absence of a TS analog in the crystal structure.
  The above figures are reprinted by permission from the AAAs: Science (2008, 319, 1387-1391) copyright 2008.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

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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.