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PDBsum entry 2b58

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protein ligands links
Transferase PDB id
2b58
Jmol
Contents
Protein chain
167 a.a. *
Ligands
COA
Waters ×82
* Residue conservation analysis
PDB id:
2b58
Name: Transferase
Title: Ssat with coa_sp, spermine disordered, k26r mutant
Structure: Diamine acetyltransferase 1. Chain: a. Synonym: spermidine/spermine n1, - acetyltransferase 1, ssa putrescine acetyltransferase, polyamine n-acetyltransferase engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: sat. Expressed in: escherichia coli. Expression_system_taxid: 562.
Resolution:
1.95Å     R-factor:   0.204     R-free:   0.253
Authors: M.C.Bewley,V.Graziano,J.S.Jiang,E.Matz,F.W.Studier,A.P.Pegg, C.S.Coleman,J.M.Flanagan,S.K.Burley,New York Sgx Research C Structural Genomics (Nysgxrc)
Key ref:
M.C.Bewley et al. (2006). Structures of wild-type and mutant human spermidine/spermine N1-acetyltransferase, a potential therapeutic drug target. Proc Natl Acad Sci U S A, 103, 2063-2068. PubMed id: 16455797 DOI: 10.1073/pnas.0511008103
Date:
27-Sep-05     Release date:   24-Jan-06    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
P21673  (SAT1_HUMAN) -  Diamine acetyltransferase 1
Seq:
Struc:
171 a.a.
167 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 1 residue position (black cross)

 Enzyme reactions 
   Enzyme class: E.C.2.3.1.57  - Diamine N-acetyltransferase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: Acetyl-CoA + an alkane-alpha,omega-diamine = CoA + an N-acetyldiamine
Acetyl-CoA
+ alkane-alpha,omega-diamine
=
CoA
Bound ligand (Het Group name = COA)
corresponds exactly
+ N-acetyldiamine
Molecule diagrams generated from .mol files obtained from the KEGG ftp site
 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     intracellular   3 terms 
  Biological process     small molecule metabolic process   9 terms 
  Biochemical function     protein binding     6 terms  

 

 
    reference    
 
 
DOI no: 10.1073/pnas.0511008103 Proc Natl Acad Sci U S A 103:2063-2068 (2006)
PubMed id: 16455797  
 
 
Structures of wild-type and mutant human spermidine/spermine N1-acetyltransferase, a potential therapeutic drug target.
M.C.Bewley, V.Graziano, J.Jiang, E.Matz, F.W.Studier, A.E.Pegg, C.S.Coleman, J.M.Flanagan.
 
  ABSTRACT  
 
Spermidine/spermine N(1)-acetyltransferase (SSAT) is a key enzyme in the control of polyamine levels in human cells, as acetylation of spermidine and spermine triggers export or degradation. Increased intracellular polyamine levels accompany several types of cancers as well as other human diseases, and compounds that affect the expression, activity, or stability of SSAT are being explored as potential therapeutic drugs. We have expressed human SSAT from the cloned cDNA in Escherichia coli and have determined high-resolution structures of wild-type and mutant SSAT, as the free dimer and in binary and ternary complexes with CoA, acetyl-CoA (AcCoA), spermine, and the inhibitor N(1),N(11)-bis-(ethyl)-norspermine (BE-3-3-3). These structures show details of binding sites for cofactor, substrates, and inhibitor and provide a framework to understand enzymatic activity, mutations, and the action of potential drugs. Two dimer conformations were observed: a symmetric form with two open surface channels capable of binding substrate or cofactor, and an asymmetric form in which only one of the surface channels appears capable of binding and acetylating polyamines. SSAT was found to self-acetylate lysine-26 in the presence of AcCoA and absence of substrate, a reaction apparently catalzyed by AcCoA bound in the second channel of the asymmetric dimer. These unexpected and intriguing complexities seem likely to have some as yet undefined role in regulating SSAT activity or stability as a part of polyamine homeostasis. Sequence signatures group SSAT with proteins that appear to have thialysine N(epsilon)-acetyltransferase activity.
 
  Selected figure(s)  
 
Figure 3.
Fig. 3. Space-filling view of the two channels on opposite surfaces of the asymmetric dimer. The channels are at the dimer interface, with chain A mostly to the upper left in the view of channel 1 and to the lower right in the view of channel 2. The two views are related by a 180° rotation about the noncrystallographic 2-fold axis. Negatively charged residues that line the channels are colored red, positively charged residues are colored blue, and hydrophobic residues are colored yellow. The suffix a or b on the amino acid designations indicates whether the residue is from chain A or B. Arrows point to the parts of channel 1 that house AcCoA and polyamine. Channel 2 is occluded by residues 27-29 of chain B, which prevents polyamine but not CoA from binding.
Figure 4.
Fig. 4. Simulated-annealing omit maps showing the electron density and interactions of bound CoA and BE-3-3-3. The electron density corresponding to CoA (A and B) and BE-3-3-3 (C) is drawn as light blue chicken wire. Oxygen atoms are red spheres, and nitrogen atoms are blue spheres. (A) Interactions of CoA that occur in both channel 1 and 2 of the asymmetric dimer. Backbone nitrogens from P-loop residues G102, F103, and G104 interact with the pyrophosphate moiety of CoA. R101, Y140, R142, and R143 side chains from the same monomer are drawn in ball-and-stick representation. (B) Hydrogen bond network with chain A residues that houses the pantetheine moiety of CoA in channel 1 of the asymmetric dimer. Side-chain residues of 94 and 95 beyond C[ ]have been omitted for clarity. Hydrogen bonds are drawn as dashed lines. (C) Interactions of BE-3-3-3 in channel 1 of the asymmetric dimer. Ball-and-stick representations of residues from chain A and B of the asymmetric dimer are drawn in purple and green, respectively.
 
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
20942800 S.B.Lee, J.H.Park, J.E.Folk, J.A.Deck, A.E.Pegg, M.Sokabe, C.S.Fraser, and M.H.Park (2010).
Inactivation of eukaryotic initiation factor 5A (eIF5A) by specific acetylation of its hypusine residue by spermidine/spermine acetyltransferase 1 (SSAT1).
  Biochem J, 433, 205-213.  
19209891 D.E.McCloskey, S.Bale, J.A.Secrist, A.Tiwari, T.H.Moss, J.Valiyaveettil, W.H.Brooks, W.C.Guida, A.E.Pegg, and S.E.Ealick (2009).
New insights into the design of inhibitors of human S-adenosylmethionine decarboxylase: studies of adenine C8 substitution in structural analogues of S-adenosylmethionine.
  J Med Chem, 52, 1388-1407.
PDB codes: 3dz2 3dz3 3dz4 3dz5 3dz6 3dz7
19332474 P.Zhou, and Z.Shang (2009).
2D molecular graphics: a flattened world of chemistry and biology.
  Brief Bioinform, 10, 247-258.  
19589128 R.A.Casero, and A.E.Pegg (2009).
Polyamine catabolism and disease.
  Biochem J, 421, 323-338.  
17464296 R.A.Casero, and L.J.Marton (2007).
Targeting polyamine metabolism and function in cancer and other hyperproliferative diseases.
  Nat Rev Drug Discov, 6, 373-390.  
17516632 S.S.Hegde, J.Chandler, M.W.Vetting, M.Yu, and J.S.Blanchard (2007).
Mechanistic and structural analysis of human spermidine/spermine N1-acetyltransferase.
  Biochemistry, 46, 7187-7195.
PDB code: 2jev
16596569 B.W.Han, C.A.Bingman, G.E.Wesenberg, and G.N.Phillips (2006).
Crystal structure of Homo sapiens thialysine Nepsilon-acetyltransferase (HsSSAT2) in complex with acetyl coenzyme A.
  Proteins, 64, 288-293.
PDB code: 2bei
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.