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PDBsum entry 1y98

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protein ligands metals Protein-protein interface(s) links
Antitumor protein PDB id
1y98
Jmol
Contents
Protein chains
211 a.a. *
12 a.a. *
Ligands
SO4
Metals
_CO
Waters ×48
* Residue conservation analysis
PDB id:
1y98
Name: Antitumor protein
Title: Structure of the brct repeats of brca1 bound to a ctip phosphopeptide.
Structure: Breast cancer type 1 susceptibility protein. Chain: a. Fragment: brct 1, brct 2. Engineered: yes. Ctip phosphorylated peptide. Chain: b. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: brca1. Expressed in: escherichia coli bl21. Expression_system_taxid: 511693. Synthetic: yes. Other_details: synthetic phosphopeptide
Biol. unit: Dimer (from PQS)
Resolution:
2.50Å     R-factor:   0.236     R-free:   0.270
Authors: A.K.Varma,R.S.Brown,G.Birrane,J.A.A.Ladias
Key ref:
A.K.Varma et al. (2005). Structural basis for cell cycle checkpoint control by the BRCA1-CtIP complex. Biochemistry, 44, 10941-10946. PubMed id: 16101277 DOI: 10.1021/bi0509651
Date:
14-Dec-04     Release date:   30-Aug-05    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
P38398  (BRCA1_HUMAN) -  Breast cancer type 1 susceptibility protein
Seq:
Struc:
 
Seq:
Struc:
 
Seq:
Struc:
 
Seq:
Struc:
1863 a.a.
211 a.a.
Protein chain
No UniProt id for this chain
Struc: 12 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     DNA repair   1 term 
  Biochemical function     DNA binding     3 terms  

 

 
DOI no: 10.1021/bi0509651 Biochemistry 44:10941-10946 (2005)
PubMed id: 16101277  
 
 
Structural basis for cell cycle checkpoint control by the BRCA1-CtIP complex.
A.K.Varma, R.S.Brown, G.Birrane, J.A.Ladias.
 
  ABSTRACT  
 
The breast and ovarian tumor suppressor BRCA1 has important functions in cell cycle checkpoint control and DNA repair. Two tandem BRCA1 C-terminal (BRCT) domains are essential for the tumor suppression activity of BRCA1 and interact in a phosphorylation-dependent manner with proteins involved in DNA damage-induced checkpoint control, including the DNA helicase BACH1 and the CtBP-interacting protein (CtIP). The crystal structure of the BRCA1 BRCT repeats bound to the PTRVSpSPVFGAT phosphopeptide corresponding to residues 322-333 of human CtIP was determined at 2.5 A resolution. The peptide binds to a cleft formed by the interface of the two BRCTs in a two-pronged manner, with phospho-Ser327 and Phe330 anchoring the peptide through extensive contacts with BRCA1 residues. Several hydrogen bonds and salt bridges that stabilize the BRCA1-BACH1 complex are missing in the BRCA1-CtIP interaction, offering a structural basis for the approximately 5-fold lower affinity of BRCA1 for CtIP compared to that of BACH1, as determined by isothermal titration calorimetry. Importantly, the side chain of Arg1775 in the cancer-associated BRCA1 mutation M1775R sterically clashes with the phenyl ring of CtIP Phe330, disrupting the BRCA1-CtIP interaction. These results provide new insights into the molecular mechanisms underlying the dynamic selection of target proteins involved in DNA repair and cell cycle control by BRCA1 and reveal how certain cancer-associated mutations affect these interactions.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
20724438 M.Rappas, A.W.Oliver, and L.H.Pearl (2011).
Structure and function of the Rad9-binding region of the DNA-damage checkpoint adaptor TopBP1.
  Nucleic Acids Res, 39, 313-324.
PDB codes: 2xnh 2xnk
20378548 P.J.Rowling, R.Cook, and L.S.Itzhaki (2010).
Toward classification of BRCA1 missense variants using a biophysical approach.
  J Biol Chem, 285, 20080-20087.  
20122900 P.R.Joseph, Z.Yuan, E.A.Kumar, G.L.Lokesh, S.Kizhake, K.Rajarathnam, and A.Natarajan (2010).
Structural characterization of BRCT-tetrapeptide binding interactions.
  Biochem Biophys Res Commun, 393, 207-210.  
  20862368 T.Ochi, B.L.Sibanda, Q.Wu, D.Y.Chirgadze, V.M.Bolanos-Garcia, and T.L.Blundell (2010).
Structural biology of DNA repair: spatial organisation of the multicomponent complexes of nonhomologous end joining.
  J Nucleic Acids, 2010, 0.  
20444606 Z.You, and J.M.Bailis (2010).
DNA damage and decisions: CtIP coordinates DNA repair and cell cycle checkpoints.
  Trends Cell Biol, 20, 402-409.  
19706752 A.De Nicolo, E.Parisini, Q.Zhong, M.Dalla Palma, K.A.Stoeckert, S.M.Domchek, K.L.Nathanson, M.A.Caligo, M.Vidal, M.E.Cusick, and J.E.Garber (2009).
Multimodal assessment of protein functional deficiency supports pathogenicity of BRCA1 p.V1688del.
  Cancer Res, 69, 7030-7037.  
19452558 I.Drikos, G.Nounesis, and C.E.Vorgias (2009).
Characterization of cancer-linked BRCA1-BRCT missense variants and their interaction with phosphoprotein targets.
  Proteins, 77, 464-476.  
18992264 M.Carvalho, M.A.Pino, R.Karchin, J.Beddor, M.Godinho-Netto, R.D.Mesquita, R.S.Rodarte, D.C.Vaz, V.A.Monteiro, S.Manoukian, M.Colombo, C.B.Ripamonti, R.Rosenquist, G.Suthers, A.Borg, P.Radice, S.A.Grist, A.N.Monteiro, and B.Billack (2009).
Analysis of a set of missense, frameshift, and in-frame deletion variants of BRCA1.
  Mutat Res, 660, 1.  
18579587 A.Kumar, W.S.Joo, G.Meinke, S.Moine, E.N.Naumova, and P.A.Bullock (2008).
Evidence for a structural relationship between BRCT domains and the helicase domains of the replication initiators encoded by the Polyomaviridae and Papillomaviridae families of DNA tumor viruses.
  J Virol, 82, 8849-8862.  
19007437 M.D.Petroski (2008).
The ubiquitin system, disease, and drug discovery.
  BMC Biochem, 9, S7.  
18676809 M.L.Kilkenny, A.S.Doré, S.M.Roe, K.Nestoras, J.C.Ho, F.Z.Watts, and L.H.Pearl (2008).
Structural and functional analysis of the Crb2-BRCT2 domain reveals distinct roles in checkpoint signaling and DNA damage repair.
  Genes Dev, 22, 2034-2047.
PDB codes: 2vxb 2vxc
18285836 M.Tischkowitz, N.Hamel, M.A.Carvalho, G.Birrane, A.Soni, E.H.van Beers, S.A.Joosse, N.Wong, D.Novak, L.A.Quenneville, S.A.Grist, P.M.Nederlof, D.E.Goldgar, S.V.Tavtigian, A.N.Monteiro, J.A.Ladias, and W.D.Foulkes (2008).
Pathogenicity of the BRCA1 missense variant M1775K is determined by the disruption of the BRCT phosphopeptide-binding pocket: a multi-modal approach.
  Eur J Hum Genet, 16, 820-832.
PDB code: 2ing
18842000 R.A.Edwards, M.S.Lee, S.E.Tsutakawa, R.S.Williams, J.A.Tainer, and J.N.Glover (2008).
The BARD1 C-terminal domain structure and interactions with polyadenylation factor CstF-50.
  Biochemistry, 47, 11446-11456.  
18717574 Y.Nominé, M.V.Botuyan, Z.Bajzer, W.G.Owen, A.J.Caride, E.Wasielewski, and G.Mer (2008).
Kinetic analysis of interaction of BRCA1 tandem breast cancer c-terminal domains with phosphorylated peptides reveals two binding conformations.
  Biochemistry, 47, 9866-9879.  
18452305 Y.Shen, and L.Tong (2008).
Structural evidence for direct interactions between the BRCT domains of human BRCA1 and a phospho-peptide from human ACC1.
  Biochemistry, 47, 5767-5773.
PDB code: 3coj
17006876 A.Ababou, and J.E.Ladbury (2007).
Survey of the year 2005: literature on applications of isothermal titration calorimetry.
  J Mol Recognit, 20, 4.  
17308087 M.A.Carvalho, S.M.Marsillac, R.Karchin, S.Manoukian, S.Grist, R.F.Swaby, T.P.Urmenyi, E.Rondinelli, R.Silva, L.Gayol, L.Baumbach, R.Sutphen, J.L.Pickard-Brzosowicz, K.L.Nathanson, A.Sali, D.Goldgar, F.J.Couch, P.Radice, and A.N.Monteiro (2007).
Determination of cancer risk associated with germ line BRCA1 missense variants by functional analysis.
  Cancer Res, 67, 1494-1501.  
17848578 M.Laufer, S.V.Nandula, A.P.Modi, S.Wang, M.Jasin, V.V.Murty, T.Ludwig, and R.Baer (2007).
Structural requirements for the BARD1 tumor suppressor in chromosomal stability and homology-directed DNA repair.
  J Biol Chem, 282, 34325-34333.  
17561994 P.Vasickova, E.Machackova, M.Lukesova, J.Damborsky, O.Horky, H.Pavlu, J.Kuklova, V.Kosinova, M.Navratilova, and L.Foretova (2007).
High occurrence of BRCA1 intragenic rearrangements in hereditary breast and ovarian cancer syndrome in the Czech Republic.
  BMC Med Genet, 8, 32.  
17305420 R.Karchin, A.N.Monteiro, S.V.Tavtigian, M.A.Carvalho, and A.Sali (2007).
Functional impact of missense variants in BRCA1 predicted by supervised learning.
  PLoS Comput Biol, 3, e26.  
16249056 G.Chinnadurai (2006).
CtIP, a candidate tumor susceptibility gene is a team player with luminaries.
  Biochim Biophys Acta, 1765, 67-73.  
17161371 J.Liu, Y.Pan, B.Ma, and R.Nussinov (2006).
"Similarity trap" in protein-protein interactions could be carcinogenic: simulations of p53 core domain complexed with 53BP1 and BRCA1 BRCT domains.
  Structure, 14, 1811-1821.  
16818604 X.Yu, S.Fu, M.Lai, R.Baer, and J.Chen (2006).
BRCA1 ubiquitinates its phosphorylation-dependent binding partner CtIP.
  Genes Dev, 20, 1721-1726.  
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.