PDBsum entry 2ger

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Oxidoreductase PDB id
Protein chains
277 a.a. *
Waters ×597
* Residue conservation analysis
PDB id:
Name: Oxidoreductase
Title: Crystal structure and oxidative mechanism of human pyrroline carboxylate reductase
Structure: Pyrroline-5-carboxylate reductase 1. Chain: a, b, c, d, e. Synonym: p5cr 1, p5c reductase 1. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 562
3.10Å     R-factor:   0.233     R-free:   0.261
Authors: Z.Meng,Z.Lou,Z.Liu,Z.Rao
Key ref:
Z.Meng et al. (2006). Crystal structure of human pyrroline-5-carboxylate reductase. J Mol Biol, 359, 1364-1377. PubMed id: 16730026 DOI: 10.1016/j.jmb.2006.04.053
20-Mar-06     Release date:   19-Sep-06    
Go to PROCHECK summary

Protein chains
Pfam   ArchSchema ?
P32322  (P5CR1_HUMAN) -  Pyrroline-5-carboxylate reductase 1, mitochondrial
319 a.a.
277 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class: E.C.  - Pyrroline-5-carboxylate reductase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]

Proline Biosynthesis
      Reaction: L-proline + NAD(P)(+) = 1-pyrroline-5-carboxylate + NAD(P)H
+ NAD(P)(+)
= 1-pyrroline-5-carboxylate
Molecule diagrams generated from .mol files obtained from the KEGG ftp site
 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     mitochondrion   2 terms 
  Biological process     small molecule metabolic process   8 terms 
  Biochemical function     oxidoreductase activity     3 terms  


DOI no: 10.1016/j.jmb.2006.04.053 J Mol Biol 359:1364-1377 (2006)
PubMed id: 16730026  
Crystal structure of human pyrroline-5-carboxylate reductase.
Z.Meng, Z.Lou, Z.Liu, M.Li, X.Zhao, M.Bartlam, Z.Rao.
Pyrroline-5-carboxylate reductase (P5CR) is a universal housekeeping enzyme that catalyzes the reduction of Delta(1)-pyrroline-5-carboxylate (P5C) to proline using NAD(P)H as the cofactor. The enzymatic cycle between P5C and proline is very important for the regulation of amino acid metabolism, intracellular redox potential, and apoptosis. Here, we present the 2.8 Angstroms resolution structure of the P5CR apo enzyme, its 3.1 Angstroms resolution ternary complex with NAD(P)H and substrate-analog. The refined structures demonstrate a decameric architecture with five homodimer subunits and ten catalytic sites arranged around a peripheral circular groove. Mutagenesis and kinetic studies reveal the pivotal roles of the dinucleotide-binding Rossmann motif and residue Glu221 in the human enzyme. Human P5CR is thermostable and the crystals were grown at 37 degrees C. The enzyme is implicated in oxidation of the anti-tumor drug thioproline.
  Selected figure(s)  
Figure 1.
Figure 1. The P5CR structure. (a) Overall view of the P5CR crystal structure. A ribbon representation of only one homodimer is shown, with each monomer presented in magenta and gold, respectively. The other four homodimers, which form the decamer, are shown in molecular surface representation. (b) The potential surface of the decamer ternary complex. The binding cofactor and substrate analog are shown as magenta spheres around the circular groove. The three dimensions are labeled and the negatively charged central channel with 25 Å diameter is shown. (c) Two views related by 90° of the monomer structure of P5CR, showing domains A and B with their secondary structure units in detail. (d) Two views related by 90° of the dimer structure of P5CR, showing how two monomers coil around each other to form one dimer. Monomers are shown in cartoon representation in magenta and gold, respectively. Secondary structure units of molecule 1 are named as αx-1; and in molecule 2 are named as αx-2. (e) Stereo view of the inter-homodimer interactions. Only two homodimers are shown at the interface. Molecules A and H, which belong to one dimer, are shown in magenta and yellow, respectively; molecules E and I, which belong to the other dimer, are drawn in green and red, respectively. There are 11 inter-homodimer, five water-mediated inter-molecular and four inntra-molecular hydrogen bonds, which form an interaction web between two homodimers. Hydrogen bonds are shown as broken cyan lines. (f) Investigation of the decamer stability with different concentrations of urea. In the Superdex200 profiles, P5CR eluted at the decamer peak when treated with no urea (black) or with 0.5 M urea (magenta). The decamer began to dissociate into dimers from 1 M urea (yellow) and 2 M urea (blue) and dissociated completely into dimers at 4 M urea (red). P5CR was refolded into a decamer from 6 M urea in Superdex200 (shown as a green curve). No monomer was observed for any concentration of urea. (g) Thermal inactivation of P5CR: (1) after incubation at various temperatures (20–75 °C) for 10 min, the relative activities of P5CR were measured at 25 °C. (2) The time-dependent thermal inactivation of P5CR was investigated at 40 °C and at 68 °C. The relative activities were measured at 25 °C and plotted against time.
Figure 3.
Figure 3. (a) Structure-based sequence alignment between P5CR in human and in different organisms as indicated. Arrows indicate β-strands; cylinders denote α-helices. Background-red residues indicate those that are conserved; background-yellow denotes residues identified to be more than 80% conserved. Residues that are important for cofactor and substrate analog binding are framed in black. (b) Superposition of P5CR from human (yellow), Neisseria meningitides Mc58 (green) and Streptococcus pyogenes (red). The α2 helix of all three structures is shown in ribbon representation and the other parts are shown as smooth lines. The NADP cofactor bound in the structure of P5CR from Streptococcus pyogenes is shown in magenta stick representation.
  The above figures are reprinted by permission from Elsevier: J Mol Biol (2006, 359, 1364-1377) copyright 2006.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
20415579 J.M.Phang, W.Liu, and O.Zabirnyk (2010).
Proline metabolism and microenvironmental stress.
  Annu Rev Nutr, 30, 441-463.  
19648921 B.Reversade, N.Escande-Beillard, A.Dimopoulou, B.Fischer, S.C.Chng, Y.Li, M.Shboul, P.Y.Tham, H.Kayserili, L.Al-Gazali, M.Shahwan, F.Brancati, H.Lee, B.D.O'Connor, M.Schmidt-von Kegler, B.Merriman, S.F.Nelson, A.Masri, F.Alkazaleh, D.Guerra, P.Ferrari, A.Nanda, A.Rajab, D.Markie, M.Gray, J.Nelson, A.Grix, A.Sommer, R.Savarirayan, A.R.Janecke, E.Steichen, D.Sillence, I.Hausser, B.Budde, G.Nürnberg, P.Nürnberg, P.Seemann, D.Kunkel, G.Zambruno, B.Dallapiccola, M.Schuelke, S.Robertson, H.Hamamy, B.Wollnik, L.Van Maldergem, S.Mundlos, and U.Kornak (2009).
Mutations in PYCR1 cause cutis laxa with progeroid features.
  Nat Genet, 41, 1016-1021.  
  19082483 Y.Ma, Z.Ding, Y.Qian, Y.W.Wan, K.Tosun, X.Shi, V.Castranova, E.J.Harner, and N.L.Guo (2009).
An integrative genomic and proteomic approach to chemosensitivity prediction.
  Int J Oncol, 34, 107-115.  
18506409 C.A.Hu, D.Bart Williams, S.Zhaorigetu, S.Khalil, G.Wan, and D.Valle (2008).
Functional genomics and SNP analysis of human genes encoding proline metabolic enzymes.
  Amino Acids, 35, 655-664.  
18369526 J.J.Tanner (2008).
Structural biology of proline catabolism.
  Amino Acids, 35, 719-730.  
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.