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PDBsum entry 2h9p
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Structural genomics, gene regulation PDB id
2h9p

 

 

 

 

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Contents
Protein chain
304 a.a. *
Ligands
ALA-ARG-THR-M3L
Waters ×263
* Residue conservation analysis
PDB id:
2h9p
Name: Structural genomics, gene regulation
Title: Wdr5 in complex with trimethylated h3k4 peptide
Structure: Wd-repeat protein 5. Chain: a. Synonym: bmp2-induced 3-kb gene protein, wdr5. Engineered: yes. H3 histone. Chain: b. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: wdr5, big3. Expressed in: escherichia coli. Expression_system_taxid: 562. Synthetic: yes. Other_details: the peptide was chemically synthesized. The sequence of the peptide is naturally found in xenopus tropicalis (western
Biol. unit: Dimer (from PQS)
Resolution:
1.91Å     R-factor:   0.166     R-free:   0.203
Authors: J.R.Min,A.Schuetz,A.Allali-Hassani,F.Martin,P.Loppnau,M.Vedadi, J.Weigelt,M.Sundstrom,A.M.Edwards,C.H.Arrowsmith,A.Bochkarev, A.N.Plotnikov,Structural Genomics Consortium (Sgc)
Key ref:
A.Schuetz et al. (2006). Structural basis for molecular recognition and presentation of histone H3 by WDR5. EMBO J, 25, 4245-4252. PubMed id: 16946699 DOI: 10.1038/sj.emboj.7601316
Date:
10-Jun-06     Release date:   01-Aug-06    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
P61964  (WDR5_HUMAN) -  WD repeat-containing protein 5 from Homo sapiens
Seq:
Struc: 		334 a.a.
304 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 

 
DOI no: 10.1038/sj.emboj.7601316 EMBO J 25:4245-4252 (2006)
PubMed id: 16946699  
 
 
Structural basis for molecular recognition and presentation of histone H3 by WDR5.
A.Schuetz, A.Allali-Hassani, F.Martín, P.Loppnau, M.Vedadi, A.Bochkarev, A.N.Plotnikov, C.H.Arrowsmith, J.Min.
 
  ABSTRACT  
 
Histone methylation at specific lysine residues brings about various downstream events that are mediated by different effector proteins. The WD40 domain of WDR5 represents a new class of histone methyl-lysine recognition domains that is important for recruiting H3K4 methyltransferases to K4-dimethylated histone H3 tail as well as for global and gene-specific K4 trimethylation. Here we report the crystal structures of full-length WDR5, WDR5Delta23 and its complexes with unmodified, mono-, di- and trimethylated histone H3K4 peptides. The structures reveal that WDR5 is able to bind all of these histone H3 peptides, but only H3K4me2 peptide forms extra interactions with WDR5 by use of both water-mediated hydrogen bonding and the altered hydrophilicity of the modified lysine 4. We propose a mechanism for the involvement of WDR5 in binding and presenting histone H3K4 for further methylation as a component of MLL complexes.
 
  Selected figure(s)  
 
Figure 4.
Figure 4 Interaction between WDR5 and histone peptides. (A) H3K4me2 peptide is shown in a stick model colored in yellow, and residues in WDR5 that make hydrogen bonds with H3K4me2 are also shown in a stick model and colored in blue. Hydrogen bonds are denoted as orange dotted lines. (B) Interaction of different states of H3K4 with Glu322 in WDR5. Dimethylated K4 is shown as a stick model colored in yellow, which interacts with Glu322 in WDR5, colored in yellow, via a water molecule. Unmodified K4 in the WDR5–H3K4 complex is colored in cyan, which is stabilized by crystal contacts. The side chain of Glu322 in this complex is either disordered or points to solvent. In the WDR5 23–H3K4me complex structure, the side chain of K4me is disordered. The side chain of Glu322 is either disordered or adopts the conformation of Glu322 in the WDR5 23–H3K4me2 complex. K4me3 in the WDR5–H3K4me3 complex is disordered, and Glu322, colored in magenta, points to solvent. 		Figure 5.
Figure 5 Detailed interaction between me2K4 in H3K4me2 and Glu322 in WDR5. (A) The H3K4me2 peptide and WDR5 are colored in yellow and blue, respectively. The electron density map is contoured at 1 . Potential water-mediated hydrogen bonds are shown as dashed orange lines. (B) The lower panel shows schematics of two alternative hydrogen binding networks involving the water molecule.
 
  The above figures are reprinted by permission from Macmillan Publishers Ltd: EMBO J (2006, 25, 4245-4252) copyright 2006.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
23211769 C.A.Musselman, M.E.Lalonde, J.Côté, and T.G.Kutateladze (2012).
Perceiving the epigenetic landscape through histone readers.
  Nat Struct Mol Biol, 19, 1218-1227.  
22231400 V.Migliori, J.Müller, S.Phalke, D.Low, M.Bezzi, W.C.Mok, S.K.Sahu, J.Gunaratne, P.Capasso, C.Bassi, V.Cecatiello, A.De Marco, W.Blackstock, V.Kuznetsov, B.Amati, M.Mapelli, and E.Guccione (2012).
Symmetric dimethylation of H3R2 is a newly identified histone mark that supports euchromatin maintenance.
  Nat Struct Mol Biol, 19, 136-144.
PDB code: 4a7j
21468892 C.Xu, and J.Min (2011).
Structure and function of WD40 domain proteins.
  Protein Cell, 2, 202-214.
PDB codes: 3e0c 3fm0 3i2n 3ow8
21107322 P.C.da Fonseca, E.H.Kong, Z.Zhang, A.Schreiber, M.A.Williams, E.P.Morris, and D.Barford (2011).
Structures of APC/C(Cdh1) with substrates identify Cdh1 and Apc10 as the D-box co-receptor.
  Nature, 470, 274-278.  
21243717 S.S.Oliver, and J.M.Denu (2011).
Dynamic interplay between histone H3 modifications and protein interpreters: emerging evidence for a "histone language".
  Chembiochem, 12, 299-307.  
21455483 T.Li, and W.G.Kelly (2011).
A role for Set1/MLL-related components in epigenetic regulation of the Caenorhabditis elegans germ line.
  PLoS Genet, 7, e1001349.  
20974918 C.Xu, C.Bian, W.Yang, M.Galka, H.Ouyang, C.Chen, W.Qiu, H.Liu, A.E.Jones, F.MacKenzie, P.Pan, S.S.Li, H.Wang, and J.Min (2010).
Binding of different histone marks differentially regulates the activity and specificity of polycomb repressive complex 2 (PRC2).
  Proc Natl Acad Sci U S A, 107, 19266-19271.
PDB codes: 3jpx 3jzg 3jzh 3jzn 3k26 3k27
20347844 J.R.England, J.Huang, M.J.Jennings, R.D.Makde, and S.Tan (2010).
RCC1 uses a conformationally diverse loop region to interact with the nucleosome: a model for the RCC1-nucleosome complex.
  J Mol Biol, 398, 518-529.  
20923397 K.L.Yap, and M.M.Zhou (2010).
Keeping it in the family: diverse histone recognition by conserved structural folds.
  Crit Rev Biochem Mol Biol, 45, 488-505.  
21072162 M.A.Adams-Cioaba, Y.Guo, C.Bian, M.F.Amaya, R.Lam, G.A.Wasney, M.Vedadi, C.Xu, and J.Min (2010).
Structural studies of the tandem Tudor domains of fragile X mental retardation related proteins FXR1 and FXR2.
  PLoS One, 5, e13559.
PDB codes: 3h8z 3o8v
20236310 M.S.Cosgrove, and A.Patel (2010).
Mixed lineage leukemia: a structure-function perspective of the MLL1 protein.
  FEBS J, 277, 1832-1842.  
20466062 M.Vedadi, C.H.Arrowsmith, A.Allali-Hassani, G.Senisterra, and G.A.Wasney (2010).
Biophysical characterization of recombinant proteins: a key to higher structural genomics success.
  J Struct Biol, 172, 107-119.  
19927323 X.H.Wu, H.Zhang, and Y.D.Wu (2010).
Is Asp-His-Ser/Thr-Trp tetrad hydrogen-bond network important to WD40-repeat proteins: a statistical and theoretical study.
  Proteins, 78, 1186-1194.  
19852741 C.Bach, and R.K.Slany (2009).
Molecular pathology of mixed-lineage leukemia.
  Future Oncol, 5, 1271-1281.  
19841675 J.Eryilmaz, P.Pan, M.F.Amaya, A.Allali-Hassani, A.Dong, M.A.Adams-Cioaba, F.Mackenzie, M.Vedadi, and J.Min (2009).
Structural studies of a four-MBT repeat protein MBTD1.
  PLoS One, 4, e7274.
PDB code: 3feo
19721463 J.Weigelt (2009).
The case for open-access chemical biology. A strategy for pre-competitive medicinal chemistry to promote drug discovery.
  EMBO Rep, 10, 941-945.  
19578375 R.C.Trievel, and A.Shilatifard (2009).
WDR5, a complexed protein.
  Nat Struct Mol Biol, 16, 678-680.  
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.  
19233876 Y.Guo, N.Nady, C.Qi, A.Allali-Hassani, H.Zhu, P.Pan, M.A.Adams-Cioaba, M.F.Amaya, A.Dong, M.Vedadi, M.Schapira, R.J.Read, C.H.Arrowsmith, and J.Min (2009).
Methylation-state-specific recognition of histones by the MBT repeat protein L3MBTL2.
  Nucleic Acids Res, 37, 2204-2210.
PDB codes: 3cey 3f70
18250626 A.Edwards (2008).
Bermuda Principles meet structural biology.
  Nat Struct Mol Biol, 15, 116.  
18829459 A.Patel, V.Dharmarajan, and M.S.Cosgrove (2008).
Structure of WDR5 Bound to Mixed Lineage Leukemia Protein-1 Peptide.
  J Biol Chem, 283, 32158-32161.
PDB code: 3eg6
18829457 A.Patel, V.E.Vought, V.Dharmarajan, and M.S.Cosgrove (2008).
A Conserved Arginine-containing Motif Crucial for the Assembly and Enzymatic Activity of the Mixed Lineage Leukemia Protein-1 Core Complex.
  J Biol Chem, 283, 32162-32175.  
18849979 A.Vitaliano-Prunier, A.Menant, M.Hobeika, V.Géli, C.Gwizdek, and C.Dargemont (2008).
Ubiquitylation of the COMPASS component Swd2 links H2B ubiquitylation to H3K4 trimethylation.
  Nat Cell Biol, 10, 1365-1371.  
18443147 J.J.Song, J.D.Garlick, and R.E.Kingston (2008).
Structural basis of histone H4 recognition by p55.
  Genes Dev, 22, 1313-1318.
PDB codes: 3c99 3c9c
18840606 J.J.Song, and R.E.Kingston (2008).
WDR5 Interacts with Mixed Lineage Leukemia (MLL) Protein via the Histone H3-binding Pocket.
  J Biol Chem, 283, 35258-35264.
PDB code: 3emh
18319736 M.M.Brent, and R.Marmorstein (2008).
Ankyrin for methylated lysines.
  Nat Struct Mol Biol, 15, 221-222.  
18538573 N.Nady, J.Min, M.S.Kareta, F.Chédin, and C.H.Arrowsmith (2008).
A SPOT on the chromatin landscape? Histone peptide arrays as a tool for epigenetic research.
  Trends Biochem Sci, 33, 305-313.  
18571423 N.V.Murzina, X.Y.Pei, W.Zhang, M.Sparkes, J.Vicente-Garcia, J.V.Pratap, S.H.McLaughlin, T.R.Ben-Shahar, A.Verreault, B.F.Luisi, and E.D.Laue (2008).
Structural basis for the recognition of histone H4 by the histone-chaperone RbAp46.
  Structure, 16, 1077-1085.
PDB codes: 3cfs 3cfv
18200608 O.Okhrimenko, and I.Jelesarov (2008).
A survey of the year 2006 literature on applications of isothermal titration calorimetry.
  J Mol Recognit, 21, 1.  
18483215 T.Suganuma, S.G.Pattenden, and J.L.Workman (2008).
Diverse functions of WD40 repeat proteins in histone recognition.
  Genes Dev, 22, 1265-1268.  
17218268 A.J.Ruthenburg, C.D.Allis, and J.Wysocka (2007).
Methylation of lysine 4 on histone H3: intricacy of writing and reading a single epigenetic mark.
  Mol Cell, 25, 15-30.  
17512990 D.W.Ng, T.Wang, M.B.Chandrasekharan, R.Aramayo, S.Kertbundit, and T.C.Hall (2007).
Plant SET domain-containing proteins: structure, function and regulation.
  Biochim Biophys Acta, 1769, 316-329.  
17898714 E.Guccione, C.Bassi, F.Casadio, F.Martinato, M.Cesaroni, H.Schuchlautz, B.Lüscher, and B.Amati (2007).
Methylation of histone H3R2 by PRMT6 and H3K4 by an MLL complex are mutually exclusive.
  Nature, 449, 933-937.  
17988933 G.Kustatscher, and A.G.Ladurner (2007).
Modular paths to 'decoding' and 'wiping' histone lysine methylation.
  Curr Opin Chem Biol, 11, 628-635.  
17227844 N.A.Larsen, J.Al-Bassam, R.R.Wei, and S.C.Harrison (2007).
Structural analysis of Bub3 interactions in the mitotic spindle checkpoint.
  Proc Natl Acad Sci U S A, 104, 1201-1206.
PDB codes: 2i3s 2i3t
17984969 R.J.Klose, and Y.Zhang (2007).
Histone H3 Arg2 methylation provides alternative directions for COMPASS.
  Nat Struct Mol Biol, 14, 1058-1060.  
17466076 S.Beltran, M.Angulo, M.Pignatelli, F.Serras, and M.Corominas (2007).
Functional dissection of the ash2 and ash1 transcriptomes provides insights into the transcriptional basis of wing phenotypes and reveals conserved protein interactions.
  Genome Biol, 8, R67.  
17984965 S.D.Taverna, H.Li, A.J.Ruthenburg, C.D.Allis, and D.J.Patel (2007).
How chromatin-binding modules interpret histone modifications: lessons from professional pocket pickers.
  Nat Struct Mol Biol, 14, 1025-1040.  
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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