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PDBsum entry 3b6g

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protein dna_rna metals Protein-protein interface(s) links
Structural protein/DNA PDB id
3b6g
Jmol PyMol
Contents
Protein chains
103 a.a. *
79 a.a. *
106 a.a. *
101 a.a. *
87 a.a. *
DNA/RNA
Metals
_MN
* Residue conservation analysis
PDB id:
3b6g
Name: Structural protein/DNA
Title: Nucleosome core particle treated with oxaliplatin
Structure: Histone h3.2. Chain: a, e. Synonym: histone h3. Engineered: yes. Histone h4. Chain: b, f. Engineered: yes. Histone h2a. Chain: c, g.
Source: Xenopus laevis. African clawed frog. Organism_taxid: 8355. Expressed in: escherichia coli. Expression_system_taxid: 562. Gene: loc494591. Homo sapiens. Human. Organism_taxid: 9606.
Resolution:
3.45Å     R-factor:   0.341     R-free:   0.435
Authors: B.Wu,C.A.Davey
Key ref:
B.Wu et al. (2008). Site selectivity of platinum anticancer therapeutics. Nat Chem Biol, 4, 110-112. PubMed id: 18157123 DOI: 10.1038/nchembio.2007.58
Date:
29-Oct-07     Release date:   25-Dec-07    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam   ArchSchema ?
P84233  (H32_XENLA) -  Histone H3.2
Seq:
Struc:
136 a.a.
103 a.a.*
Protein chain
Pfam   ArchSchema ?
P62799  (H4_XENLA) -  Histone H4
Seq:
Struc:
103 a.a.
79 a.a.
Protein chains
Pfam   ArchSchema ?
P06897  (H2A1_XENLA) -  Histone H2A type 1
Seq:
Struc:
130 a.a.
106 a.a.*
Protein chains
Pfam   ArchSchema ?
P02281  (H2B11_XENLA) -  Histone H2B 1.1
Seq:
Struc:
126 a.a.
101 a.a.*
Protein chain
Pfam   ArchSchema ?
P62799  (H4_XENLA) -  Histone H4
Seq:
Struc:
103 a.a.
87 a.a.
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 3 residue positions (black crosses)

 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     nucleus   4 terms 
  Biological process     transcription initiation, DNA-dependent   1 term 
  Biochemical function     protein binding     3 terms  

 

 
DOI no: 10.1038/nchembio.2007.58 Nat Chem Biol 4:110-112 (2008)
PubMed id: 18157123  
 
 
Site selectivity of platinum anticancer therapeutics.
B.Wu, P.Dröge, C.A.Davey.
 
  ABSTRACT  
 
X-ray crystallographic and biochemical investigation of the reaction of cisplatin and oxaliplatin with nucleosome core particle and naked DNA reveals that histone octamer association can modulate DNA platination. Adduct formation also occurs at specific histone methionine residues, which could serve as a nuclear platinum reservoir influencing adduct transfer to DNA. Our findings suggest that the nucleosome center may provide a favorable target for the design of improved platinum anticancer drugs.
 
  Selected figure(s)  
 
Figure 1.
Histone adducts occur at H3M120 and H4M84, and DNA adduct sites are numbered for cisPt (1, 5–7) and oxPt (1–4, 8, 9). The central base pair at the NCP pseudo two-fold symmetry axis is denoted by a red arrow. An apostrophe indicates the opposing NCP half. (a–c) Anomalous difference maps, contoured at 4 (a), 4.1 (b) and 3.4 (c) and superimposed on the refined models for 48-h oxPt (a,b) and cisPt (c) treatments, show platinum atom locations (black mesh). (a) View of a thin slice of the NCP. DNA strands are colored orange/cyan and histone proteins are colored blue (H3), green (H4), yellow (H2A) and red (H2B). (b) An oxPt-AG adduct. (c) cisPt adducts at GA and methionine in the NCP center. (d) DNA sequence and adduct sites (underlined) for 79 of 147 base pairs. (e) Summary of cisPt and oxPt adduct sites, with approximately one NCP half shown. Methionine sites are circled, and magenta arrows show corresponding locations in the opposing NCP half. DNA strands and histone proteins are colored as in a. (d,e) Bases (b) with major versus minor groove facing inward toward the histone octamer are colored, respectively, black and orange (d) or black and white (e). (f) Model of an oxPt adduct at the NCP center. An oxPt-GG adduct from the oligonucleotide crystal structure^17 was modified to an oxPt-GA adduct and superimposed onto the oxPt1 site adjacent to the central base pair in the high-resolution NCP crystal structure^12. The platinum (magenta) and diaminocyclohexane atoms are shown in space-filling representation to emphasize potential interactions with histone elements, such as H3K115 and H3K115' (black arrows). The atomic coordinates and structure factors for cisPt- and oxPt-treated NCP were deposited in the Protein Data Bank under accession codes 3B6F and 3B6G, respectively.
Figure 2.
NCP and naked DNA were treated with cisPt or oxPt (color-coded), followed by end labeling of the purified DNA and exonuclease III digestion (Supplementary Methods). Before fragment separation by denaturing gel electrophoresis, samples were deplatinated with thiourea to eliminate migration retardation resulting from the presence of adducts^8. This allows determination of adduct sites at approximately base-pair resolution in comparison with a modified Maxam-Gilbert purine-sequencing standard (m), in which the 3'-phosphate groups have been removed by polynucleotide kinase treatment to yield the same 3'-OH ends that arise from exonuclease cleavage. Red arrow denotes central bases. (a–c) Denaturing PAGE of exonuclease-treated DNA samples shows digest termination sites resulting from encounter of platinum adducts. Overall footprint (a) and resolved sections corresponding to the central (b) and 3' (c) regions are shown. (d) DNA sequence for 79 of 147 base pairs. Regions where the DNA minor groove faces inward, toward the histone octamer, are colored orange. Exonuclease stop sites are depicted as arrowheads adjacent to the terminal 3' nucleotide, pointing toward the apparent platinum adduct. Filled symbols indicate relatively strong termination points, and open symbols indicate moderate termination points.
*Note: In the version of this article initially published online, dash marks indicating the position of molecular weight markers in Figure 2a are missing. The error has been corrected for all versions of the article.
 
  The above figures are reprinted by permission from Macmillan Publishers Ltd: Nat Chem Biol (2008, 4, 110-112) copyright 2008.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
  21344528 B.Wu, M.S.Ong, M.Groessl, Z.Adhireksan, C.G.Hartinger, P.J.Dyson, and C.A.Davey (2011).
A ruthenium antimetastasis agent forms specific histone protein adducts in the nucleosome core.
  Chemistry, 17, 3562-3566.
PDB code: 3mnn
21497773 D.Ziliak, P.H.O'Donnell, H.K.Im, E.R.Gamazon, P.Chen, S.Delaney, S.Shukla, S.Das, N.J.Cox, E.E.Vokes, E.E.Cohen, M.E.Dolan, and R.S.Huang (2011).
Germline polymorphisms discovered via a cell-based, genome-wide approach predict platinum response in head and neck cancers.
  Transl Res, 157, 265-272.  
21268159 F.Arnesano, B.D.Belviso, R.Caliandro, G.Falini, S.Fermani, G.Natile, and D.Siliqi (2011).
Crystallographic analysis of metal-ion binding to human ubiquitin.
  Chemistry, 17, 1569-1578.
PDB codes: 3n30 3n32
21176878 S.Tan, and C.A.Davey (2011).
Nucleosome structural studies.
  Curr Opin Struct Biol, 21, 128-136.  
20082287 A.Bouslimani, N.Bec, M.Glueckmann, C.Hirtz, and C.Larroque (2010).
Matrix-assisted laser desorption/ionization imaging mass spectrometry of oxaliplatin derivatives in heated intraoperative chemotherapy (HIPEC)-like treated rat kidney.
  Rapid Commun Mass Spectrom, 24, 415-421.  
20931644 A.Casini, C.Temperini, C.Gabbiani, C.T.Supuran, and L.Messori (2010).
The x-ray structure of the adduct between NAMI-A and carbonic anhydrase provides insights into the reactivity of this metallodrug with proteins.
  ChemMedChem, 5, 1989-1994.
PDB code: 3m1j
20026584 G.E.Davey, B.Wu, Y.Dong, U.Surana, and C.A.Davey (2010).
DNA stretching in the nucleosome facilitates alkylation by an intercalating antitumour agent.
  Nucleic Acids Res, 38, 2081-2088.
PDB code: 3kuy
20878805 J.M.Zimbron, A.Sardo, T.Heinisch, T.Wohlschlager, J.Gradinaru, C.Massa, T.Schirmer, M.Creus, and T.R.Ward (2010).
Chemo-genetic optimization of DNA recognition by metallodrugs using a presenter-protein strategy.
  Chemistry, 16, 12883-12889.
PDB code: 2wpu
20494975 K.Mohideen, R.Muhammad, and C.A.Davey (2010).
Perturbations in nucleosome structure from heavy metal association.
  Nucleic Acids Res, 38, 6301-6311.
PDB codes: 3mgp 3mgq 3mgr 3mgs
20393316 P.H.O'Donnell, E.Gamazon, W.Zhang, A.L.Stark, E.O.Kistner-Griffin, R.Stephanie Huang, and M.Eileen Dolan (2010).
Population differences in platinum toxicity as a means to identify novel genetic susceptibility variants.
  Pharmacogenet Genomics, 20, 327-337.  
21168769 R.C.Todd, and S.J.Lippard (2010).
Consequences of cisplatin binding on nucleosome structure and dynamics.
  Chem Biol, 17, 1334-1343.
PDB code: 3o62
19340883 E.Jerremalm, I.Wallin, and H.Ehrsson (2009).
New insights into the biotransformation and pharmacokinetics of oxaliplatin.
  J Pharm Sci, 98, 3879-3885.  
19884901 N.H.Nicolay, D.P.Berry, and R.A.Sharma (2009).
Liver metastases from colorectal cancer: radioembolization with systemic therapy.
  Nat Rev Clin Oncol, 6, 687-697.  
19040246 P.J.Sadler (2009).
Protein recognition of platinated DNA.
  Chembiochem, 10, 73-74.  
  20046924 R.C.Todd, and S.J.Lippard (2009).
Inhibition of transcription by platinum antitumor compounds.
  Metallomics, 1, 280-291.  
19289051 S.Balasubramanian, F.Xu, and W.K.Olson (2009).
DNA sequence-directed organization of chromatin: structure-based computational analysis of nucleosome-binding sequences.
  Biophys J, 96, 2245-2260.  
18940663 B.Wu, and C.A.Davey (2008).
Platinum drug adduct formation in the nucleosome core alters nucleosome mobility but not positioning.
  Chem Biol, 15, 1023-1028.  
18924284 G.E.Davey, and C.A.Davey (2008).
Chromatin - a new, old drug target?
  Chem Biol Drug Des, 72, 165-170.  
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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