PDBsum entry 1wp4

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Oxidoreductase PDB id
Protein chains
288 a.a. *
SO4 ×4
NDP ×4
Waters ×744
* Residue conservation analysis
PDB id:
Name: Oxidoreductase
Title: Structure of tt368 protein from thermus thermophilus hb8
Structure: 3-hydroxyisobutyrate dehydrogenase. Chain: a, b, c, d. Synonym: dehydrogenase. Engineered: yes
Source: Thermus thermophilus. Organism_taxid: 300852. Strain: hb8. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008.
Biol. unit: Tetramer (from PQS)
2.00Å     R-factor:   0.182     R-free:   0.208
Authors: N.K.Lokanath,N.Kunishima,Riken Structural Genomics/proteomic Initiative (Rsgi)
Key ref:
N.K.Lokanath et al. (2005). Crystal structure of novel NADP-dependent 3-hydroxyisobutyrate dehydrogenase from Thermus thermophilus HB8. J Mol Biol, 352, 905-917. PubMed id: 16126223 DOI: 10.1016/j.jmb.2005.07.068
30-Aug-04     Release date:   30-Aug-05    
Go to PROCHECK summary

Protein chains
Pfam   ArchSchema ?
Q5SLQ6  (Q5SLQ6_THET8) -  3-hydroxyisobutyrate dehydrogenase
289 a.a.
288 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Gene Ontology (GO) functional annotation 
  GO annot!
  Biological process     oxidation-reduction process   3 terms 
  Biochemical function     nucleotide binding     7 terms  


DOI no: 10.1016/j.jmb.2005.07.068 J Mol Biol 352:905-917 (2005)
PubMed id: 16126223  
Crystal structure of novel NADP-dependent 3-hydroxyisobutyrate dehydrogenase from Thermus thermophilus HB8.
N.K.Lokanath, N.Ohshima, K.Takio, I.Shiromizu, C.Kuroishi, N.Okazaki, S.Kuramitsu, S.Yokoyama, M.Miyano, N.Kunishima.
3-Hydroxyisobutyrate, a central metabolite in the valine catabolic pathway, is reversibly oxidized to methylmalonate semialdehyde by a specific dehydrogenase belonging to the 3-hydroxyacid dehydrogenase family. To gain insight into the function of this enzyme at the atomic level, we have determined the first crystal structures of the 3-hydroxyisobutyrate dehydrogenase from Thermus thermophilus HB8: holo enzyme and sulfate ion complex. The crystal structures reveal a unique tetrameric oligomerization and a bound cofactor NADP+. This bacterial enzyme may adopt a novel cofactor-dependence on NADP, whereas NAD is preferred in eukaryotic enzymes. The protomer folds into two distinct domains with open/closed interdomain conformations. The cofactor NADP+ with syn nicotinamide and the sulfate ion are bound to distinct sites located at the interdomain cleft of the protomer through an induced-fit domain closure upon cofactor binding. From the structural comparison with the crystal structure of 6-phosphogluconate dehydrogenase, another member of the 3-hydroxyacid dehydrogenase family, it is suggested that the observed sulfate ion and the substrate 3-hydroxyisobutyrate share the same binding pocket. The observed oligomeric state might be important for the catalytic function through forming the active site involving two adjacent subunits, which seems to be conserved in the 3-hydroxyacid dehydrogenases. A kinetic study confirms that this enzyme has strict substrate specificity for 3-hydroxyisobutyrate and serine, but it cannot distinguish the chirality of the substrates. Lys165 is likely the catalytic residue of the enzyme.
  Selected figure(s)  
Figure 1.
Figure 1. Catabolic pathway of valine. The step catalyzed by HIBADH is boxed.
Figure 5.
Figure 5. Comparison of binding ligands between HIBADH and 6PGDH in stereo views. (a) NADP+/sulfate binding in the sulfate ion complex form of HIBADH. NADP+ and important residues are depicted as ball-and-stick models and labeled. Residues of the domains I and II of a protomer are colored yellow and green, respectively. Residues from the other subunit are shown in light blue. (b) Close-up view of the sulfate binding adjacent to the nicotinamide ring of NADP+ molecule. Important hydrogen bonds are indicated by broken lines. (c) Close-up view of the cofactor/substrate binding in 6PGDH with the presentation equivalent to (b). The active NADP+ analogue nicotinamide-8-bromo-adenine dinucleotide phosphate (Nbr8ADP+), the substrate 6-phosphogluconate (6PG) and the catalytic general base Lys183 are shown. This picture is produced from a superposition of the cofactor molecule in the Nbr8ADP+-6PGDH complex (PDB, 1PGN) to the 6PG-6PGDH complex structure (PDB, 1PGP).
  The above figures are reprinted by permission from Elsevier: J Mol Biol (2005, 352, 905-917) copyright 2005.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
20876192 S.Mondal, C.Nagao, and K.Mizuguchi (2010).
Detecting subtle functional differences in ketopantoate reductase and related enzymes using a rule-based approach with sequence-structure homology recognition scores.
  Protein Eng Des Sel, 23, 859-869.  
  21048868 S.Ueshima, H.Muramatsu, T.Nakajima, H.Yamamoto, S.Kato, H.Misono, and S.Nagata (2010).
Identification, Cloning, and Characterization of l-Phenylserine Dehydrogenase from Pseudomonas syringae NK-15.
  Enzyme Res, 2010, 597010.  
19517068 T.Yao, L.Xu, H.Ying, H.Huang, and M.Yan (2010).
The catalytic property of 3-hydroxyisobutyrate dehydrogenase from Bacillus cereus on 3-hydroxypropionate.
  Appl Biochem Biotechnol, 160, 694-703.  
18677553 M.Sugahara, Y.Asada, K.Shimizu, H.Yamamoto, N.K.Lokanath, H.Mizutani, B.Bagautdinov, Y.Matsuura, M.Taketa, Y.Kageyama, N.Ono, Y.Morikawa, Y.Tanaka, H.Shimada, T.Nakamoto, M.Sugahara, M.Yamamoto, and N.Kunishima (2008).
High-throughput crystallization-to-structure pipeline at RIKEN SPring-8 Center.
  J Struct Funct Genomics, 9, 21-28.  
17570834 W.He, Y.Wang, W.Liu, and C.Z.Zhou (2007).
Crystal structure of Saccharomyces cerevisiae 6-phosphogluconate dehydrogenase Gnd1.
  BMC Struct Biol, 7, 38.
PDB code: 2p4q
16650981 A.Andreeva, and A.G.Murzin (2006).
Evolution of protein fold in the presence of functional constraints.
  Curr Opin Struct Biol, 16, 399-408.  
16513644 W.Sun, S.Singh, R.Zhang, J.L.Turnbull, and D.Christendat (2006).
Crystal structure of prephenate dehydrogenase from Aquifex aeolicus. Insights into the catalytic mechanism.
  J Biol Chem, 281, 12919-12928.
PDB code: 2g5c
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.