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PDBsum entry 2uxn
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protein ligands metals Protein-protein interface(s) links
Oxidoreductase/transcription regulator PDB id
2uxn

 

 

 

 

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Contents
Protein chains
664 a.a. *
133 a.a. *
Ligands
ALA-ARG-THR-LYP-
GLN-THR-ALA
FDA
GOL
Metals
_CL ×2
Waters ×51
* Residue conservation analysis
PDB id:
2uxn
Name: Oxidoreductase/transcription regulator
Title: Structural basis of histone demethylation by lsd1 revealed by suicide inactivation
Structure: Lysine-specific histone demethylase 1. Chain: a. Fragment: swirm domain, amine oxidase domain and linker, residues 171-836. Synonym: flavin-containing amine oxidase domain-containing protein 2, braf35-hdac complex protein bhc110, lysine-specific demethylase 1. Engineered: yes. Rest corepressor 1. Chain: b.
Source: Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 511693. Synthetic: yes. Organism_taxid: 9606
Resolution:
2.72Å     R-factor:   0.242     R-free:   0.272
Authors: M.Yang,J.C.Culhane,L.M.Szewczuk,C.B.Gocke,C.A.Brautigam,D.R.Tomchick, M.Machius,P.A.Cole,H.Yu
Key ref:
M.Yang et al. (2007). Structural basis of histone demethylation by LSD1 revealed by suicide inactivation. Nat Struct Biol, 14, 535-539. PubMed id: 17529991 DOI: 10.1038/nsmb1255
Date:
28-Mar-07     Release date:   29-May-07    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
O60341  (KDM1A_HUMAN) -  Lysine-specific histone demethylase 1A from Homo sapiens
Seq:
Struc: 		 
Seq:
Struc: 		852 a.a.
664 a.a.
Protein chain
Pfam   ArchSchema ?
Q9UKL0  (RCOR1_HUMAN) -  REST corepressor 1 from Homo sapiens
Seq:
Struc: 		485 a.a.
133 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class: Chain A: E.C.1.14.99.66  - [histone-H3]-N(6),N(6)-dimethyl-L-lysine(4) FAD-dependent demethylase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: N6,N6-dimethyl-L-lysyl4-[histone H3] + 2 A + 2 H2O = L-lysyl4- [histone H3] + 2 formaldehyde + 2 AH2
N(6),N(6)-dimethyl-L-lysyl(4)-[histone H3]
 + 2 × A
 + 2 × H2O
 = L-lysyl(4)- [histone H3]
 +
2 × formaldehyde
Bound ligand (Het Group name = ALA)
matches with 40.00% similarity 		+ 2 × AH2
Molecule diagrams generated from .mol files obtained from the KEGG ftp site

 

 
    Key reference    
 
 
DOI no: 10.1038/nsmb1255 Nat Struct Biol 14:535-539 (2007)
PubMed id: 17529991  
 
 
Structural basis of histone demethylation by LSD1 revealed by suicide inactivation.
M.Yang, J.C.Culhane, L.M.Szewczuk, C.B.Gocke, C.A.Brautigam, D.R.Tomchick, M.Machius, P.A.Cole, H.Yu.
 
  ABSTRACT  
 
Histone methylation regulates diverse chromatin-templated processes, including transcription. The recent discovery of the first histone lysine-specific demethylase (LSD1) has changed the long-held view that histone methylation is a permanent epigenetic mark. LSD1 is a flavin adenine dinucleotide (FAD)-dependent amine oxidase that demethylates histone H3 Lys4 (H3-K4). However, the mechanism by which LSD1 achieves its substrate specificity is unclear. We report the crystal structure of human LSD1 with a propargylamine-derivatized H3 peptide covalently tethered to FAD. H3 adopts three consecutive gamma-turns, enabling an ideal side chain spacing that places its N terminus into an anionic pocket and positions methyl-Lys4 near FAD for catalysis. The LSD1 active site cannot productively accommodate more than three residues on the N-terminal side of the methyllysine, explaining its H3-K4 specificity. The unusual backbone conformation of LSD1-bound H3 suggests a strategy for designing potent LSD1 inhibitors with therapeutic potential.
 
  Selected figure(s)  
 
Figure 1.
(a) Chemical structures of N-methylpropargyl-K4 H3[1–21], its covalent adduct with FAD, and the NaBH[4]-reduced adduct. (b) Stereo view of the structure of the N-methylpropargyl-K4 H3[1–21]–FAD adduct in stick representation, overlaid with a simulated-annealing composite-omit map contoured at 1.2 . (c) Overall structure of LSD1–CoREST–H3. The FAD-H3 adduct is shown in stick representation. All structural figures were generated with PyMOL (http://pymol.sourceforge.net). 		Figure 2.
(a) Residues 1–7 of the H3 peptide (yellow tube) interact with the active site cavity of LSD1. Molecular surface of LSD1 AOD and SWIRM is colored by electrostatic potential: red, negative; blue, positive. Dashed yellow line represents C-terminal portion of H3, which might bind at a surface groove between AOD and SWIRM, according to existing biochemical evidence^8, ^9. (b) Binding of H3 at the active site of LSD1. Yellow, H3; purple, LSD1. (c) Binding of an H3K4me3 peptide to the PHD finger of BPTF (PDB 2FUU). Color scheme is as in b. (d) Stereo view of an H3K4me3 peptide bound to the PHD finger of ING2 (PDB 2G6Q). The distance between the C atoms of Arg2 and Thr6 is 13.1 Å. (e) Stereo view of the derivatized H3 peptide bound to LSD1 (same scale as e). Dashed red lines represent the hydrogen bonds of the three -turns. The distance between the C atoms of Arg2 and Thr6 is 9.2 Å. (f) Schematic drawing of interactions between LSD1 and the H3 peptide, highlighting the anionic pocket and the serpentine H3 backbone conformation that results from the three -turns.
 
  The above figures are reprinted by permission from Macmillan Publishers Ltd: Nat Struct Biol (2007, 14, 535-539) copyright 2007.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
  21141727 A.K.Upadhyay, and X.Cheng (2011).
Dynamics of histone lysine methylation: structures of methyl writers and erasers.
  Prog Drug Res, 67, 107-124.  
20951770 R.A.Varier, and H.T.Timmers (2011).
Histone lysine methylation and demethylation pathways in cancer.
  Biochim Biophys Acta, 1815, 75-89.  
20333681 S.Hayami, J.D.Kelly, H.S.Cho, M.Yoshimatsu, M.Unoki, T.Tsunoda, H.I.Field, D.E.Neal, H.Yamaue, B.A.Ponder, Y.Nakamura, and R.Hamamoto (2011).
Overexpression of LSD1 contributes to human carcinogenesis through chromatin regulation in various cancers.
  Int J Cancer, 128, 574-586.  
20228790 E.Metzger, A.Imhof, D.Patel, P.Kahl, K.Hoffmeyer, N.Friedrichs, J.M.Müller, H.Greschik, J.Kirfel, S.Ji, N.Kunowska, C.Beisenherz-Huss, T.Günther, R.Buettner, and R.Schüle (2010).
Phosphorylation of histone H3T6 by PKCbeta(I) controls demethylation at histone H3K4.
  Nature, 464, 792-796.  
20148560 J.C.Culhane, D.Wang, P.M.Yen, and P.A.Cole (2010).
Comparative analysis of small molecules and histone substrate analogues as LSD1 lysine demethylase inhibitors.
  J Am Chem Soc, 132, 3164-3176.  
20210752 M.L.Bellows, and C.A.Floudas (2010).
Computational methods for de novo protein design and its applications to the human immunodeficiency virus 1, purine nucleoside phosphorylase, ubiquitin specific protease 7, and histone demethylases.
  Curr Drug Targets, 11, 264-278.  
20373914 N.Mosammaparast, and Y.Shi (2010).
Reversal of histone methylation: biochemical and molecular mechanisms of histone demethylases.
  Annu Rev Biochem, 79, 155-179.  
20389281 Y.Lin, Y.Wu, J.Li, C.Dong, X.Ye, Y.I.Chi, B.M.Evers, and B.P.Zhou (2010).
The SNAG domain of Snail1 functions as a molecular hook for recruiting lysine-specific demethylase 1.
  EMBO J, 29, 1803-1816.  
19464317 B.Illi, C.Colussi, A.Grasselli, A.Farsetti, M.C.Capogrossi, and C.Gaetano (2009).
NO sparks off chromatin: tales of a multifaceted epigenetic regulator.
  Pharmacol Ther, 123, 344-352.  
19624733 F.Forneris, E.Battaglioli, A.Mattevi, and C.Binda (2009).
New roles of flavoproteins in molecular cell biology: histone demethylase LSD1 and chromatin.
  FEBS J, 276, 4304-4312.  
18923809 S.S.Ng, W.W.Yue, U.Oppermann, and R.J.Klose (2009).
Dynamic protein methylation in chromatin biology.
  Cell Mol Life Sci, 66, 407-422.  
18343668 F.Forneris, C.Binda, E.Battaglioli, and A.Mattevi (2008).
LSD1: oxidative chemistry for multifaceted functions in chromatin regulation.
  Trends Biochem Sci, 33, 181-189.  
18800048 P.A.Cole (2008).
Chemical probes for histone-modifying enzymes.
  Nat Chem Biol, 4, 590-597.  
18426222 T.A.White, W.H.Johnson, C.P.Whitman, and J.J.Tanner (2008).
Structural basis for the inactivation of Thermus thermophilus proline dehydrogenase by N-propargylglycine.
  Biochemistry, 47, 5573-5580.
PDB code: 2ekg
17988933 G.Kustatscher, and A.G.Ladurner (2007).
Modular paths to 'decoding' and 'wiping' histone lysine methylation.
  Curr Opin Chem Biol, 11, 628-635.  
17851108 J.C.Culhane, and P.A.Cole (2007).
LSD1 and the chemistry of histone demethylation.
  Curr Opin Chem Biol, 11, 561-568.  
17897944 R.Anand, and R.Marmorstein (2007).
Structure and mechanism of lysine-specific demethylase enzymes.
  J Biol Chem, 282, 35425-35429.  
17984971 S.Lall (2007).
Primers on chromatin.
  Nat Struct Mol Biol, 14, 1110-1115.  
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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