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Oxidoreductase/transcription regulator PDB id
2iw5
Jmol
Contents
Protein chains
666 a.a. *
133 a.a. *
Ligands
FAD
GOL ×2
NH4
Metals
_CL ×3
Waters ×78
* Residue conservation analysis
PDB id:
2iw5
Name: Oxidoreductase/transcription regulator
Title: Structural basis for corest-dependent demethylation of nucleosomes by the human lsd1 histone demethylase
Structure: Lysine-specific histone demethylase 1. Chain: a. Fragment: swirm domain, amine oxidase domain and linker, re 171-836. Synonym: amine oxidase flavin-containing domain protein 2, braf35-hdac complex protein bhc110. Engineered: yes. Rest corepressor 1. Chain: b.
Source: Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 511693.
Biol. unit: Dimer (from PDB file)
Resolution:
2.57Å     R-factor:   0.204     R-free:   0.212
Authors: M.Yang,C.B.Gocke,X.Luo,D.Borek,D.R.Tomchick,M.Machius,Z.Otwi H.Yu
Key ref:
M.Yang et al. (2006). Structural basis for CoREST-dependent demethylation of nucleosomes by the human LSD1 histone demethylase. Mol Cell, 23, 377-387. PubMed id: 16885027 DOI: 10.1016/j.molcel.2006.07.012
Date:
26-Jun-06     Release date:   09-Aug-06    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
O60341  (KDM1A_HUMAN) -  Lysine-specific histone demethylase 1A
Seq:
Struc: 		 
Seq:
Struc: 		852 a.a.
666 a.a.
Protein chain
Pfam   ArchSchema ?
Q9UKL0  (RCOR1_HUMAN) -  REST corepressor 1
Seq:
Struc: 		482 a.a.
133 a.a.
Key:    PfamA domain  PfamB domain  Secondary structure  CATH domain

 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     nucleus   1 term 
  Biological process     oxidation-reduction process   3 terms 
  Biochemical function     protein binding     4 terms  

 

 
DOI no: 10.1016/j.molcel.2006.07.012 Mol Cell 23:377-387 (2006)
PubMed id: 16885027  
 
 
Structural basis for CoREST-dependent demethylation of nucleosomes by the human LSD1 histone demethylase.
M.Yang, C.B.Gocke, X.Luo, D.Borek, D.R.Tomchick, M.Machius, Z.Otwinowski, H.Yu.
 
  ABSTRACT  
 
Histone methylation regulates diverse chromatin-templated processes, including transcription. Many transcriptional corepressor complexes contain lysine-specific demethylase 1 (LSD1) and CoREST that collaborate to demethylate mono- and dimethylated H3-K4 of nucleosomes. Here, we report the crystal structure of the LSD1-CoREST complex. LSD1-CoREST forms an elongated structure with a long stalk connecting the catalytic domain of LSD1 and the CoREST SANT2 domain. LSD1 recognizes a large segment of the H3 tail through a deep, negatively charged pocket at the active site and possibly a shallow groove on its surface. CoREST SANT2 interacts with DNA. Disruption of the SANT2-DNA interaction diminishes CoREST-dependent demethylation of nucleosomes by LSD1. The shape and dimension of LSD1-CoREST suggest its bivalent binding to nucleosomes, allowing efficient H3-K4 demethylation. This spatially separated, multivalent nucleosome binding mode may apply to other chromatin-modifying enzymes that generally contain multiple nucleosome binding modules.
 
  Selected figure(s)  
 
Figure 1.
Figure 1. Structure of LSD1-CoREST
(A) Mechanism of LSD1-catalyzed demethylation of H3-K4. The carbon atom that is oxidized to form formaldehyde is shown in red.
(B) Domain structures of human LSD1 (AAH48134) and CoREST. The boundaries of proteins used in crystallization are indicated.
(C) Overall structure of LSD1-CoREST. The color scheme for this and subsequent figures is similar to that used in (B): SWIRM, blue; AOD_N, yellow; AOD_C, gold; LSD1 insert, green; CoREST linker, pink; and CoREST SANT2, red. The FAD is shown in stick representation in this and subsequent figures. The red arrow indicates the active site. All structural figures were generated with PyMOL.
Figure 2.
Figure 2. Structure of the Amine Oxidase Domain of LSD1
(A) Ribbon drawing of the structure of LSD1 amine oxidase domain (AOD) and a portion of the CoREST linker. The structural elements lining the rim of the active site are colored blue. The location of the LSD1 insert is indicated.
(B) Ribbon drawing of the structure of maize PAO. The regions in mPAO that correspond to AOD_N and AOD_C in LSD1 are colored yellow and gold, respectively. The structural elements lining the rim of the active site are colored blue.
(C) Overlay of the active site residues of mPAO and LSD1. The ribbons of mPAO and LSD1 are colored cyan and gray, respectively. The active site residues of mPAO and LSD1 are shown as cyan and yellow sticks, respectively. Only FAD in LSD1 is shown for clarity.
(D) Molecular surface of the active site of LSD1 AOD in similar orientation as in (A) with the positive and negative electrostatic potentials colored blue and red, respectively.
(E) Molecular surface of the active site of mPAO in similar orientation as in (B) with superimposed positive and negative electrostatic potentials colored blue and red, respectively. The two openings of the long active site tunnel are indicated.
 
  The above figures are reprinted by permission from Cell Press: Mol Cell (2006, 23, 377-387) copyright 2006.  
  Figures were selected by the author.  

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.  
20832726 D.van Essen, Y.Zhu, and S.Saccani (2010).
A feed-forward circuit controlling inducible NF-κB target gene activation by promoter histone demethylation.
  Mol Cell, 39, 750-760.  
20202279 L.Attig, A.Gabory, and C.Junien (2010).
Nutritional developmental epigenomics: immediate and long-lasting effects.
  Proc Nutr Soc, 69, 221-231.  
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.  
20567261 Y.Yang, L.Hu, P.Wang, H.Hou, Y.Lin, Y.Liu, Z.Li, R.Gong, X.Feng, L.Zhou, W.Zhang, Y.Dong, H.Yang, H.Lin, Y.Wang, C.D.Chen, and Y.Xu (2010).
Structural insights into a dual-specificity histone demethylase ceKDM7A from Caenorhabditis elegans.
  Cell Res, 20, 886-898.
PDB codes: 3n9l 3n9m 3n9n 3n9o 3n9p 3n9q
19407342 A.Karytinos, F.Forneris, A.Profumo, G.Ciossani, E.Battaglioli, C.Binda, and A.Mattevi (2009).
A novel mammalian flavin-dependent histone demethylase.
  J Biol Chem, 284, 17775-17782.  
19173732 D.Zheng, K.Zhao, and M.F.Mehler (2009).
Profiling RE1/REST-mediated histone modifications in the human genome.
  Genome Biol, 10, R9.  
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.  
19193804 H.Gu, and B.Roizman (2009).
Engagement of the lysine-specific demethylase/HDAC1/CoREST/REST complex by herpes simplex virus 1.
  J Virol, 83, 4376-4385.  
19394292 J.Ouyang, Y.Shi, A.Valin, Y.Xuan, and G.Gill (2009).
Direct binding of CoREST1 to SUMO-2/3 contributes to gene-specific repression by the LSD1/CoREST1/HDAC complex.
  Mol Cell, 34, 145-154.  
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.  
18657505 A.V.Gómez, D.Galleguillos, J.C.Maass, E.Battaglioli, M.Kukuljan, and M.E.Andrés (2008).
CoREST represses the heat shock response mediated by HSF1.
  Mol Cell, 31, 222-231.  
18806873 C.B.Gocke, and H.Yu (2008).
ZNF198 stabilizes the LSD1-CoREST-HDAC1 complex on chromatin through its MYM-type zinc fingers.
  PLoS ONE, 3, e3255.  
18184656 E.B.Dammer, and M.B.Sewer (2008).
Phosphorylation of CtBP1 by cAMP-dependent protein kinase modulates induction of CYP17 by stimulating partnering of CtBP1 and 2.
  J Biol Chem, 283, 6925-6934.  
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.  
18691967 N.Ding, H.Zhou, P.O.Esteve, H.G.Chin, S.Kim, X.Xu, S.M.Joseph, M.J.Friez, C.E.Schwartz, S.Pradhan, and T.G.Boyer (2008).
Mediator links epigenetic silencing of neuronal gene expression with x-linked mental retardation.
  Mol Cell, 31, 347-359.  
18451103 P.A.Cloos, J.Christensen, K.Agger, and K.Helin (2008).
Erasing the methyl mark: histone demethylases at the center of cellular differentiation and disease.
  Genes Dev, 22, 1115-1140.  
18940868 R.Gatta, and R.Mantovani (2008).
NF-Y substitutes H2A-H2B on active cell-cycle promoters: recruitment of CoREST-KDM1 and fine-tuning of H3 methylations.
  Nucleic Acids Res, 36, 6592-6607.  
18950507 X.Zhou, and H.Ma (2008).
Evolutionary history of histone demethylase families: distinct evolutionary patterns suggest functional divergence.
  BMC Evol Biol, 8, 294.  
18037899 A.J.Ruthenburg, H.Li, D.J.Patel, and C.D.Allis (2007).
Multivalent engagement of chromatin modifications by linked binding modules.
  Nat Rev Mol Cell Biol, 8, 983-994.  
17713579 E.V.Benevolenskaya (2007).
Histone H3K4 demethylases are essential in development and differentiation.
  Biochem Cell Biol, 85, 435-443.  
17537733 F.Forneris, C.Binda, A.Adamo, E.Battaglioli, and A.Mattevi (2007).
Structural basis of LSD1-CoREST selectivity in histone H3 recognition.
  J Biol Chem, 282, 20070-20074.
PDB code: 2v1d
17434129 F.Lan, M.Zaratiegui, J.Villén, M.W.Vaughn, A.Verdel, M.Huarte, Y.Shi, S.P.Gygi, D.Moazed, R.A.Martienssen, and Y.Shi (2007).
S. pombe LSD1 homologs regulate heterochromatin propagation and euchromatic gene transcription.
  Mol Cell, 26, 89.  
17996704 F.Liu, V.Quesada, P.Crevillén, I.Bäurle, S.Swiezewski, and C.Dean (2007).
The Arabidopsis RNA-binding protein FCA requires a lysine-specific demethylase 1 homolog to downregulate FLC.
  Mol Cell, 28, 398-407.  
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.  
17934479 K.L.Rice, I.Hormaeche, and J.D.Licht (2007).
Epigenetic regulation of normal and malignant hematopoiesis.
  Oncogene, 26, 6697-6714.  
17511474 L.M.Szewczuk, J.C.Culhane, M.Yang, A.Majumdar, H.Yu, and P.A.Cole (2007).
Mechanistic analysis of a suicide inactivator of histone demethylase LSD1.
  Biochemistry, 46, 6892-6902.  
17572692 L.Ooi, and I.C.Wood (2007).
Chromatin crosstalk in development and disease: lessons from REST.
  Nat Rev Genet, 8, 544-554.  
17529991 M.Yang, J.C.Culhane, L.M.Szewczuk, C.B.Gocke, C.A.Brautigam, D.R.Tomchick, M.Machius, P.A.Cole, and H.Yu (2007).
Structural basis of histone demethylation by LSD1 revealed by suicide inactivation.
  Nat Struct Mol Biol, 14, 535-539.
PDB code: 2uxn
17504018 P.Stavropoulos, and A.Hoelz (2007).
Lysine-specific demethylase 1 as a potential therapeutic target.
  Expert Opin Ther Targets, 11, 809-820.  
17897944 R.Anand, and R.Marmorstein (2007).
Structure and mechanism of lysine-specific demethylase enzymes.
  J Biol Chem, 282, 35425-35429.  
17342184 R.J.Klose, and Y.Zhang (2007).
Regulation of histone methylation by demethylimination and demethylation.
  Nat Rev Mol Cell Biol, 8, 307-318.  
17984971 S.Lall (2007).
Primers on chromatin.
  Nat Struct Mol Biol, 14, 1110-1115.  
17275397 V.Joosten, and W.J.van Berkel (2007).
Flavoenzymes.
  Curr Opin Chem Biol, 11, 195-202.  
17277881 X.Tian, and J.Fang (2007).
Current perspectives on histone demethylases.
  Acta Biochim Biophys Sin (Shanghai), 39, 81-88.  
17988851 X.Zhu, J.Wang, B.G.Ju, and M.G.Rosenfeld (2007).
Signaling and epigenetic regulation of pituitary development.
  Curr Opin Cell Biol, 19, 605-611.  
17218267 Y.Shi, and J.R.Whetstine (2007).
Dynamic regulation of histone lysine methylation by demethylases.
  Mol Cell, 25, 1.  
17567753 Z.Chen, J.Zang, J.Kappler, X.Hong, F.Crawford, Q.Wang, F.Lan, C.Jiang, J.Whetstine, S.Dai, K.Hansen, Y.Shi, and G.Zhang (2007).
Structural basis of the recognition of a methylated histone tail by JMJD2A.
  Proc Natl Acad Sci U S A, 104, 10818-10823.
PDB codes: 2p5b 2pxj
16987819 F.Forneris, C.Binda, A.Dall'Aglio, M.W.Fraaije, E.Battaglioli, and A.Mattevi (2006).
A highly specific mechanism of histone H3-K4 recognition by histone demethylase LSD1.
  J Biol Chem, 281, 35289-35295.  
17070031 J.F.Couture, and R.C.Trievel (2006).
Histone-modifying enzymes: encrypting an enigmatic epigenetic code.
  Curr Opin Struct Biol, 16, 753-760.  
17070680 L.De Colibus, and A.Mattevi (2006).
New frontiers in structural flavoenzymology.
  Curr Opin Struct Biol, 16, 722-728.  
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.