PDBsum entry 1t2u

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Antitumor protein PDB id
Protein chain
207 a.a. *
SO4 ×2
Waters ×51
* Residue conservation analysis
PDB id:
Name: Antitumor protein
Title: Structural basis of phosphopeptide recognition by the brct d brca1: structure of brca1 missense variant v1809f
Structure: Breast cancer type 1 susceptibility protein. Chain: a. Fragment: brct domain 1646-1859. Engineered: yes. Mutation: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: brca1. Expressed in: escherichia coli. Expression_system_taxid: 562
2.80Å     R-factor:   0.277     R-free:   0.294
Authors: R.S.Williams,M.S.Lee,D.D.Duong,J.N.M.Glover
Key ref:
R.S.Williams et al. (2004). Structural basis of phosphopeptide recognition by the BRCT domain of BRCA1. Nat Struct Mol Biol, 11, 519-525. PubMed id: 15133503 DOI: 10.1038/nsmb776
22-Apr-04     Release date:   11-May-04    
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Protein chain
Pfam   ArchSchema ?
P38398  (BRCA1_HUMAN) -  Breast cancer type 1 susceptibility protein
1863 a.a.
207 a.a.*
Key:    PfamA domain  PfamB domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 1 residue position (black cross)

 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: 10.1038/nsmb776 Nat Struct Mol Biol 11:519-525 (2004)
PubMed id: 15133503  
Structural basis of phosphopeptide recognition by the BRCT domain of BRCA1.
R.S.Williams, M.S.Lee, D.D.Hau, J.N.Glover.
The BRCT repeats in BRCA1 are essential for its tumor suppressor activity and interact with phosphorylated protein targets containing the sequence pSer-X-X-Phe, where X indicates any residue. The structure of the tandem BRCA1 BRCT repeats bound to an optimized phosphopeptide reveals that the N-terminal repeat harbors a conserved BRCT phosphoserine-binding pocket, while the interface between the repeats forms a hydrophobic groove that recognizes the phenylalanine. Crystallographic and biochemical data suggest that the structural integrity of both binding sites is essential for peptide recognition. The diminished peptide-binding capacity observed for cancer-associated BRCA1-BRCT variants may explain the enhanced cancer risks associated with these mutations.
  Selected figure(s)  
Figure 1.
Figure 1. Overview of the BRCA1 BRCT -peptide complex. (a) -strands in the BRCT domain are green and -helices are yellow. The peptide is blue. The BRCT residues that recognize the pSer and Phe(+3) residues have transparent surfaces. (b) Amino acid sequence of the human BRCA1 BRCT domain with secondary structure. The residues that contact the phosphoserine are shaded blue, and those that form the Phe(+3)-binding pocket are marked by red circles. Missense mutations assayed for interactions with the peptide are above the sequence. Residues involved in inter-repeat BRCT interactions are boxed. (c) Structural arrangement of one of the three similar dimers in the crystallographic asymmetric unit.
Figure 2.
Figure 2. Details of BRCA1 BRCT -peptide interactions. (a) Stereo view of key residues that recognize the pSer and Phe(+3) residues of the peptide. Hydrogen bonds and salt bridges are indicated by dotted lines. (b) Conformational variability of phosphopeptide binding. Overlay of the five independent peptide structures in the crystallographic asymmetric unit. The BRCT C atoms of each of the BRCT -peptide complexes were superimposed to generate the overlay. (c) Electrostatic surface representation of the BRCT domain with the pSer- and Phe-binding pockets; the peptide is gray.
  The above figures are reprinted by permission from Macmillan Publishers Ltd: Nat Struct Mol Biol (2004, 11, 519-525) copyright 2004.  
  Figures were selected by the author.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
  19937654 C.C.Leung, E.Kellogg, A.Kuhnert, F.Hänel, D.Baker, and J.N.Glover (2010).
Insights from the crystal structure of the sixth BRCT domain of topoisomerase IIbeta binding protein 1.
  Protein Sci, 19, 162-167.
PDB code: 3jve
20094029 J.S.Williams, R.S.Williams, C.L.Dovey, G.Guenther, J.A.Tainer, and P.Russell (2010).
gammaH2A binds Brc1 to maintain genome integrity during S-phase.
  EMBO J, 29, 1136-1148.
PDB codes: 3l40 3l41
20177395 M.E.Moynahan, and M.Jasin (2010).
Mitotic homologous recombination maintains genomic stability and suppresses tumorigenesis.
  Nat Rev Mol Cell Biol, 11, 196-207.  
19925808 M.W.Richards, J.W.Leung, S.M.Roe, K.Li, J.Chen, and R.Bayliss (2010).
A pocket on the surface of the N-terminal BRCT domain of Mcph1 is required to prevent abnormal chromosome condensation.
  J Mol Biol, 395, 908-915.
PDB code: 2wt8
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.  
20159462 S.J.Campbell, R.A.Edwards, and J.N.Glover (2010).
Comparison of the structures and peptide binding specificities of the BRCT domains of MDC1 and BRCA1.
  Structure, 18, 167-176.
PDB codes: 3k05 3k0h 3k0k 3k15 3k16
20808856 S.Rajasekaran, T.Mi, J.C.Merlin, A.Oommen, P.Gradie, and M.R.Schiller (2010).
Partitioning of minimotifs based on function with improved prediction accuracy.
  PLoS One, 5, e12276.  
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.  
19804755 R.S.Williams, G.E.Dodson, O.Limbo, Y.Yamada, J.S.Williams, G.Guenther, S.Classen, J.N.Glover, H.Iwasaki, P.Russell, and J.A.Tainer (2009).
Nbs1 flexibly tethers Ctp1 and Mre11-Rad50 to coordinate DNA double-strand break processing and repair.
  Cell, 139, 87-99.
PDB codes: 3hue 3huf
19187758 T.Usui, S.S.Foster, and J.H.Petrini (2009).
Maintenance of the DNA-damage checkpoint requires DNA-damage-induced mediator protein oligomerization.
  Mol Cell, 33, 147-159.  
18628483 A.De Nicolo, M.Tancredi, G.Lombardi, C.C.Flemma, S.Barbuti, C.Di Cristofano, B.Sobhian, G.Bevilacqua, R.Drapkin, and M.A.Caligo (2008).
A novel breast cancer-associated BRIP1 (FANCJ/BACH1) germ-line mutation impairs protein stability and function.
  Clin Cancer Res, 14, 4672-4680.  
19026779 A.Ghosh, S.Shuman, and C.D.Lima (2008).
The structure of Fcp1, an essential RNA polymerase II CTD phosphatase.
  Mol Cell, 32, 478-490.
PDB codes: 3ef0 3ef1
18772227 A.Kinner, W.Wu, C.Staudt, and G.Iliakis (2008).
Gamma-H2AX in recognition and signaling of DNA double-strand breaks in the context of chromatin.
  Nucleic Acids Res, 36, 5678-5694.  
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.  
18582474 C.Xu, L.Wu, G.Cui, M.V.Botuyan, J.Chen, and G.Mer (2008).
Structure of a second BRCT domain identified in the nijmegen breakage syndrome protein Nbs1 and its function in an MDC1-dependent localization of Nbs1 to DNA damage sites.
  J Mol Biol, 381, 361-372.
PDB code: 2k2w
18951449 F.J.Couch, L.J.Rasmussen, R.Hofstra, A.N.Monteiro, M.S.Greenblatt, Wind, P.Boffetta, F.Couch, Wind, D.Easton, D.Eccles, W.Foulkes, M.Genuardi, D.Goldgar, M.Greenblatt, R.Hofstra, F.Hogervorst, N.Hoogerbrugge, S.Plon, P.Radice, L.Rasmussen, O.Sinilnikova, A.Spurdle, and S.V.Tavtigian (2008).
Assessment of functional effects of unclassified genetic variants.
  Hum Mutat, 29, 1314-1326.  
17620310 J.Brunet, A.Vazquez-Martin, R.Colomer, B.Graña-Suarez, B.Martin-Castillo, and J.A.Menendez (2008).
BRCA1 and acetyl-CoA carboxylase: the metabolic syndrome of breast cancer.
  Mol Carcinog, 47, 157-163.  
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.  
18854158 R.S.Williams, G.Moncalian, J.S.Williams, Y.Yamada, O.Limbo, D.S.Shin, L.M.Groocock, D.Cahill, C.Hitomi, G.Guenther, D.Moiani, J.P.Carney, P.Russell, and J.A.Tainer (2008).
Mre11 dimers coordinate DNA end bridging and nuclease processing in double-strand-break repair.
  Cell, 135, 97.
PDB codes: 3dsc 3dsd
17902052 T.Anagnostopoulos, M.Pertesi, I.Konstantopoulou, S.Armaou, S.Kamakari, G.Nasioulas, A.Athanasiou, A.Dobrovic, M.A.Young, D.Goldgar, G.Fountzilas, and D.Yannoukakos (2008).
G1738R is a BRCA1 founder mutation in Greek breast/ovarian cancer patients: evaluation of its pathogenicity and inferences on its genealogical history.
  Breast Cancer Res Treat, 110, 377-385.  
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
17063491 C.A.Gough, T.Gojobori, and T.Imanishi (2007).
Cancer-related mutations in BRCA1-BRCT cause long-range structural changes in protein-protein binding sites: a molecular dynamics study.
  Proteins, 66, 69-86.  
17915942 E.F.DeRose, M.W.Clarkson, S.A.Gilmore, C.J.Galban, A.Tripathy, J.M.Havener, G.A.Mueller, D.A.Ramsden, R.E.London, and A.L.Lee (2007).
Solution structure of polymerase mu's BRCT Domain reveals an element essential for its role in nonhomologous end joining.
  Biochemistry, 46, 12100-12110.
PDB code: 2htf
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.  
17189298 M.Hölzel, T.Grimm, M.Rohrmoser, A.Malamoussi, T.Harasim, A.Gruber-Eber, E.Kremmer, and D.Eick (2007).
The BRCT domain of mammalian Pes1 is crucial for nucleolar localization and rRNA processing.
  Nucleic Acids Res, 35, 789-800.  
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.  
17713585 R.S.Williams, J.S.Williams, and J.A.Tainer (2007).
Mre11-Rad50-Nbs1 is a keystone complex connecting DNA repair machinery, double-strand break signaling, and the chromatin template.
  Biochem Cell Biol, 85, 509-520.  
17643121 Z.Liu, J.Wu, and X.Yu (2007).
CCDC98 targets BRCA1 to DNA damage sites.
  Nat Struct Mol Biol, 14, 716-720.  
17094803 D.C.Zappulla, A.S.Maharaj, J.J.Connelly, R.A.Jockusch, and R.Sternglanz (2006).
Rtt107/Esc4 binds silent chromatin and DNA repair proteins using different BRCT motifs.
  BMC Mol Biol, 7, 40.  
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.  
16528612 J.N.Glover (2006).
Insights into the molecular basis of human hereditary breast cancer from studies of the BRCA1 BRCT domain.
  Fam Cancer, 5, 89-93.  
16361700 M.Kobayashi, F.Figaroa, N.Meeuwenoord, L.E.Jansen, and G.Siegal (2006).
Characterization of the DNA binding and structural properties of the BRCT region of human replication factor C p140 subunit.
  J Biol Chem, 281, 4308-4317.  
15923272 P.K.Lovelock, S.Healey, W.Au, E.Y.Sum, A.Tesoriero, E.M.Wong, S.Hinson, R.Brinkworth, A.Bekessy, O.Diez, L.Izatt, E.Solomon, M.Jenkins, H.Renard, J.Hopper, P.Waring, S.V.Tavtigian, D.Goldgar, G.J.Lindeman, J.E.Visvader, F.J.Couch, B.R.Henderson, M.Southey, G.Chenevix-Trench, A.B.Spurdle, and M.A.Brown (2006).
Genetic, functional, and histopathological evaluation of two C-terminal BRCA1 missense variants.
  J Med Genet, 43, 74-83.  
16715518 S.Agata, A.Viel, L.Della Puppa, L.Cortesi, G.Fersini, M.Callegaro, M.Dalla Palma, R.Dolcetti, M.Federico, S.Venuta, G.Miolo, E.D'Andrea, and M.Montagna (2006).
Prevalence of BRCA1 genomic rearrangements in a large cohort of Italian breast and breast/ovarian cancer families without detectable BRCA1 and BRCA2 point mutations.
  Genes Chromosomes Cancer, 45, 791-797.  
15576564 B.A.Joughin, B.Tidor, and M.B.Yaffe (2005).
A computational method for the analysis and prediction of protein:phosphopeptide-binding sites.
  Protein Sci, 14, 131-139.  
16049003 M.S.Lee, R.A.Edwards, G.L.Thede, and J.N.Glover (2005).
Structure of the BRCT repeat domain of MDC1 and its specificity for the free COOH-terminal end of the gamma-H2AX histone tail.
  J Biol Chem, 280, 32053-32056.
PDB code: 2ado
16377563 M.Stucki, J.A.Clapperton, D.Mohammad, M.B.Yaffe, S.J.Smerdon, and S.P.Jackson (2005).
MDC1 directly binds phosphorylated histone H2AX to regulate cellular responses to DNA double-strand breaks.
  Cell, 123, 1213-1226.
PDB code: 2azm
16333323 R.S.Williams, N.Bernstein, M.S.Lee, M.L.Rakovszky, D.Cui, R.Green, M.Weinfeld, and J.N.Glover (2005).
Structural basis for phosphorylation-dependent signaling in the DNA-damage response.
  Biochem Cell Biol, 83, 721-727.  
16116421 W.L.Bridge, C.J.Vandenberg, R.J.Franklin, and K.Hiom (2005).
The BRIP1 helicase functions independently of BRCA1 in the Fanconi anemia pathway for DNA crosslink repair.
  Nat Genet, 37, 953-957.  
15341721 G.Charier, J.Couprie, B.Alpha-Bazin, V.Meyer, E.Quéméneur, R.Guérois, I.Callebaut, B.Gilquin, and S.Zinn-Justin (2004).
The Tudor tandem of 53BP1: a new structural motif involved in DNA and RG-rich peptide binding.
  Structure, 12, 1551-1562.
PDB code: 1ssf
15133502 J.A.Clapperton, I.A.Manke, D.M.Lowery, T.Ho, L.F.Haire, M.B.Yaffe, and S.J.Smerdon (2004).
Structure and mechanism of BRCA1 BRCT domain recognition of phosphorylated BACH1 with implications for cancer.
  Nat Struct Mol Biol, 11, 512-518.
PDB code: 1t15
15501676 J.N.Glover, R.S.Williams, and M.S.Lee (2004).
Interactions between BRCT repeats and phosphoproteins: tangled up in two.
  Trends Biochem Sci, 29, 579-585.  
15485915 X.Yu, and J.Chen (2004).
DNA damage-induced cell cycle checkpoint control requires CtIP, a phosphorylation-dependent binding partner of BRCA1 C-terminal domains.
  Mol Cell Biol, 24, 9478-9486.  
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.