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PDBsum entry 1nlw

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protein dna_rna Protein-protein interface(s) links
Transcription/DNA PDB id
1nlw
Jmol
Contents
Protein chains
79 a.a. *
76 a.a. *
DNA/RNA
Waters ×251
* Residue conservation analysis
PDB id:
1nlw
Name: Transcription/DNA
Title: Crystal structure of mad-max recognizing DNA
Structure: 5'- d( Gp Ap Gp Tp Ap Gp Cp Ap Cp Gp Tp Gp Cp Tp Ap Cp Tp C)- 3'. Chain: f, g, h, j. Engineered: yes. Mad protein. Chain: a, d. Fragment: bhlhz region. Synonym: max dimerizer.
Source: Synthetic: yes. Homo sapiens. Human. Organism_taxid: 9606. Gene: mad. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008. Gene: max.
Biol. unit: Tetramer (from PQS)
Resolution:
2.00Å     R-factor:   0.264     R-free:   0.324
Authors: S.K.Nair,S.K.Burley
Key ref:
S.K.Nair and S.K.Burley (2003). X-ray structures of Myc-Max and Mad-Max recognizing DNA. Molecular bases of regulation by proto-oncogenic transcription factors. Cell, 112, 193-205. PubMed id: 12553908 DOI: 10.1016/S0092-8674(02)01284-9
Date:
07-Jan-03     Release date:   04-Feb-03    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam   ArchSchema ?
Q05195  (MAD1_HUMAN) -  Max dimerization protein 1
Seq:
Struc:
221 a.a.
79 a.a.*
Protein chains
Pfam   ArchSchema ?
P61244  (MAX_HUMAN) -  Protein max
Seq:
Struc:
160 a.a.
76 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!
  Biochemical function     protein dimerization activity     1 term  

 

 
DOI no: 10.1016/S0092-8674(02)01284-9 Cell 112:193-205 (2003)
PubMed id: 12553908  
 
 
X-ray structures of Myc-Max and Mad-Max recognizing DNA. Molecular bases of regulation by proto-oncogenic transcription factors.
S.K.Nair, S.K.Burley.
 
  ABSTRACT  
 
X-ray structures of the basic/helix-loop-helix/leucine zipper (bHLHZ) domains of Myc-Max and Mad-Max heterodimers bound to their common DNA target (Enhancer or E box hexanucleotide, 5'-CACGTG-3') have been determined at 1.9 A and 2.0 A resolution, respectively. E box recognition by these two structurally similar transcription factor pairs determines whether a cell will divide and proliferate (Myc-Max) or differentiate and become quiescent (Mad-Max). Deregulation of Myc has been implicated in the development of many human cancers, including Burkitt's lymphoma, neuroblastomas, and small cell lung cancers. Both quasisymmetric heterodimers resemble the symmetric Max homodimer, albeit with marked structural differences in the coiled-coil leucine zipper regions that explain preferential homo- and heteromeric dimerization of these three evolutionarily related DNA-binding proteins. The Myc-Max heterodimer, but not its Mad-Max counterpart, dimerizes to form a bivalent heterotetramer, which explains how Myc can upregulate expression of genes with promoters bearing widely separated E boxes.
 
  Selected figure(s)  
 
Figure 2.
Figure 2. Structures of Myc-Max and Mad-Max Heterodimers Bound to DNAMolscript (Kraulis, 1991)/Raster3D (Merritt and Murphy, 1994) drawing showing the overall topology of the Myc-Max/DNA (A) and Mad-Max (B) cocrystal structures. Color coding: Myc-cyan, Max-red, and Mad-green. Cocrystallization oligonucleotide is shown as an atomic stick figure. The helix, basic region, and zipper regions have been designated on the Myc-Max/DNA structure.
Figure 5.
Figure 5. Bivalent Myc-Max Heterotetramer(A) Ribbon diagrams of the bivalent Myc-Max heterotetramer observed in the Myc-Max/DNA cocrystals.(B) GRASP (Nicholls et al., 1991) molecular surface rendition of one heterodimer with α carbon backbone representation (cyan and red) of the other. The view is orthogonal to the orientation in Figure 5A. Salt bridges and hydrogen bonds, burying nearly 1400 Å^2 of solvent-accessible surface area, mediate packing interactions between the two heterodimers. The polarity of many of the residues in Myc that comprise this interaction network is altered in Mad and this alteration in polarity of the residues that stabilize the interaction of the Myc-Max heterotetramer may explain the lack of tetramer formation by Mad-Max heterodimers.(C) Size exclusion profile of the Myc-Max heterodimer. Approximately, 300 μM of the heterodimer was loaded onto a Superdex 75 column (Pharmacia) and representative fractions from the elution run are shown on a Coomassie blue-stained SDS/PAGE gel. Elution volumes for four calibration standards are noted on the chromatogram. Myc-Max elutes at a position corresponding to a relative molecular mass of approximately 40 kDa corresponding to the expected size of the Myc-Max heterotetramer observed in the crystals.(D) Hydrodynamic characterization of the Myc-Max bivalent heterotetramer. Sedimentation equilibrium data were collected at 280 nm with a rotor speed of 20,000 rpm at a temperature of 20^°C using a Beckman XL-A ultracentrifuge. The fit corresponds to a two-component model with a tethered Myc-Max dimer to Myc-Max tetramer association constants of 90 nM. The residuals of the fit are shown in the lower image. Data analysis utilized the NONLIN program (http://www.cauma.uthscsa.edu/software).
 
  The above figures are reprinted by permission from Cell Press: Cell (2003, 112, 193-205) copyright 2003.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
21685915 I.Comino-Méndez, F.J.Gracia-Aznárez, F.Schiavi, I.Landa, L.J.Leandro-García, R.Letón, E.Honrado, R.Ramos-Medina, D.Caronia, G.Pita, A.Gómez-Graña, A.A.de Cubas, L.Inglada-Pérez, A.Maliszewska, E.Taschin, S.Bobisse, G.Pica, P.Loli, R.Hernández-Lavado, J.A.Díaz, M.Gómez-Morales, A.González-Neira, G.Roncador, C.Rodríguez-Antona, J.Benítez, M.Mannelli, G.Opocher, M.Robledo, and A.Cascón (2011).
Exome sequencing identifies MAX mutations as a cause of hereditary pheochromocytoma.
  Nat Genet, 43, 663-667.  
21243688 L.P.Hernández-Eguía, R.J.Brea, L.Castedo, P.Ballester, and J.R.Granja (2011).
Regioisomeric control induced by DABCO coordination to rotatable self-assembled bis- and tetraporphyrin α,γ-cyclic octapeptide dimers.
  Chemistry, 17, 1220-1229.  
21245039 N.Hao, M.L.Whitelaw, K.E.Shearwin, I.B.Dodd, and A.Chapman-Smith (2011).
Identification of residues in the N-terminal PAS domains important for dimerization of Arnt and AhR.
  Nucleic Acids Res, 39, 3695-3709.  
20979085 R.J.Brea, M.J.Pérez-Alvite, M.Panciera, M.Mosquera, L.Castedo, and J.R.Granja (2011).
Highly efficient and directional homo- and heterodimeric energy transfer materials based on fluorescently derivatized α,γ-cyclic octapeptides.
  Chem Asian J, 6, 110-121.  
20395165 A.N.Koehler (2010).
A complex task? Direct modulation of transcription factors with small molecules.
  Curr Opin Chem Biol, 14, 331-340.  
20086039 J.Xu, A.T.De Jong, G.Chen, H.K.Chow, C.O.Damaso, A.Schwartz Mittelman, and J.A.Shin (2010).
Reengineering natural design by rational design and in vivo library selection: the HLH subdomain in bHLHZ proteins is a unique requirement for DNA-binding function.
  Protein Eng Des Sel, 23, 337-346.  
20142507 M.Hartl, A.M.Mitterstiller, T.Valovka, K.Breuker, B.Hobmayer, and K.Bister (2010).
Stem cell-specific activation of an ancestral myc protooncogene with conserved basic functions in the early metazoan Hydra.
  Proc Natl Acad Sci U S A, 107, 4051-4056.  
20170194 O.Ecevit, M.A.Khan, and D.J.Goss (2010).
Kinetic analysis of the interaction of b/HLH/Z transcription factors Myc, Max, and Mad with cognate DNA.
  Biochemistry, 49, 2627-2635.  
20334529 R.Rohs, X.Jin, S.M.West, R.Joshi, B.Honig, and R.S.Mann (2010).
Origins of specificity in protein-DNA recognition.
  Annu Rev Biochem, 79, 233-269.  
19035580 E.M.Jouaux, B.B.Timm, K.M.Arndt, and T.E.Exner (2009).
Improving the interaction of Myc-interfering peptides with Myc using molecular dynamics simulations.
  J Pept Sci, 15, 5.  
19189276 F.O.McDuff, J.F.Naud, M.Montagne, S.Sauvé, and P.Lavigne (2009).
The Max homodimeric b-HLH-LZ significantly interferes with the specific heterodimerization between the c-Myc and Max b-HLH-LZ in absence of DNA: a quantitative analysis.
  J Mol Recognit, 22, 261-269.  
19498040 H.Jiang, K.E.Bower, A.E.Beuscher, B.Zhou, A.A.Bobkov, A.J.Olson, and P.K.Vogt (2009).
Stabilizers of the Max homodimer identified in virtual ligand screening inhibit Myc function.
  Mol Pharmacol, 76, 491-502.  
19449889 J.Xu, G.Chen, A.T.De Jong, S.H.Shahravan, and J.A.Shin (2009).
Max-E47, a designed minimalist protein that targets the E-box DNA site in vivo and in vitro.
  J Am Chem Soc, 131, 7839-7848.  
19683038 K.Bitra, A.Tan, A.Dowling, and S.R.Palli (2009).
Functional characterization of PAS and HES family bHLH transcription factors during the metamorphosis of the red flour beetle, Tribolium castaneum.
  Gene, 448, 74-87.  
19423669 M.Naganuma, S.Sekine, R.Fukunaga, and S.Yokoyama (2009).
Unique protein architecture of alanyl-tRNA synthetase for aminoacylation, editing, and dimerization.
  Proc Natl Acad Sci U S A, 106, 8489-8494.
PDB codes: 2ztg 2zvf
19568423 R.K.Mailer, K.Falk, and O.Rötzschke (2009).
Absence of leucine zipper in the natural FOXP3Delta2Delta7 isoform does not affect dimerization but abrogates suppressive capacity.
  PLoS One, 4, e6104.  
19841254 S.J.Maerkl, and S.R.Quake (2009).
Experimental determination of the evolvability of a transcription factor.
  Proc Natl Acad Sci U S A, 106, 18650-18655.  
19022175 A.V.Follis, D.I.Hammoudeh, H.Wang, E.V.Prochownik, and S.J.Metallo (2008).
Structural rationale for the coupled binding and unfolding of the c-Myc oncoprotein by small molecules.
  Chem Biol, 15, 1149-1155.  
18199329 B.Schuster-Böckler, and A.Bateman (2008).
Protein interactions in human genetic diseases.
  Genome Biol, 9, R9.  
19165923 D.Steiger, M.Furrer, D.Schwinkendorf, and P.Gallant (2008).
Max-independent functions of Myc in Drosophila melanogaster.
  Nat Genet, 40, 1084-1091.  
18566588 E.P.Lamber, L.Vanhille, L.C.Textor, G.S.Kachalova, M.H.Sieweke, and M.Wilmanns (2008).
Regulation of the transcription factor Ets-1 by DNA-mediated homo-dimerization.
  EMBO J, 27, 2006-2017.
PDB code: 2nny
17827227 E.P.Lamber, M.Wilmanns, and D.I.Svergun (2008).
Low resolution structural models of the basic helix-loop-helix leucine zipper domain of upstream stimulatory factor 1 and its complexes with DNA from small angle X-ray scattering data.
  Biophys J, 94, 193-197.  
18949049 H.K.Chow, J.Xu, S.H.Shahravan, A.T.De Jong, G.Chen, and J.A.Shin (2008).
Hybrids of the bHLH and bZIP protein motifs display different DNA-binding activities in vivo vs. in vitro.
  PLoS ONE, 3, e3514.  
18515839 M.Gao, and J.Skolnick (2008).
DBD-Hunter: a knowledge-based method for the prediction of DNA-protein interactions.
  Nucleic Acids Res, 36, 3978-3992.  
18473392 N.Krauss, H.Wessner, K.Welfle, H.Welfle, C.Scholz, M.Seifert, K.Zubow, J.Aÿ, M.Hahn, P.Scheerer, A.Skerra, and W.Höhne (2008).
The structure of the anti-c-myc antibody 9E10 Fab fragment/epitope peptide complex reveals a novel binding mode dominated by the heavy chain hypervariable loops.
  Proteins, 73, 552-565.
PDB codes: 2or9 2orb
18706517 T.Berg (2008).
Inhibition of transcription factors with small organic molecules.
  Curr Opin Chem Biol, 12, 464-471.  
18925859 Y.Chen, and O.I.Olopade (2008).
MYC in breast tumor progression.
  Expert Rev Anticancer Ther, 8, 1689-1698.  
18177499 Y.Nakahata, M.Yoshida, A.Takano, H.Soma, T.Yamamoto, A.Yasuda, T.Nakatsu, and T.Takumi (2008).
A direct repeat of E-box-like elements is required for cell-autonomous circadian rhythm of clock genes.
  BMC Mol Biol, 9, 1.  
17315254 A.Kiessling, R.Wiesinger, B.Sperl, and T.Berg (2007).
Selective Inhibition of c-Myc/Max Dimerization by a Pyrazolo[1,5-a]pyrimidine.
  ChemMedChem, 2, 627-630.  
17438293 A.V.Morozov, and E.D.Siggia (2007).
Connecting protein structure with predictions of regulatory sites.
  Proc Natl Acad Sci U S A, 104, 7068-7073.  
17171690 A.Wozniak, R.Sciot, L.Guillou, P.Pauwels, B.Wasag, M.Stul, J.R.Vermeesch, P.Vandenberghe, J.Limon, and M.Debiec-Rychter (2007).
Array CGH analysis in primary gastrointestinal stromal tumors: cytogenetic profile correlates with anatomic site and tumor aggressiveness, irrespective of mutational status.
  Genes Chromosomes Cancer, 46, 261-276.  
17826759 C.L.Pickett, K.T.Breen, and D.E.Ayer (2007).
A C. elegans Myc-like network cooperates with semaphorin and Wnt signaling pathways to control cell migration.
  Dev Biol, 310, 226-239.  
16964280 F.Reiter, M.Hartl, A.I.Karagiannidis, and K.Bister (2007).
WS5, a direct target of oncogenic transcription factor Myc, is related to human melanoma glycoprotein genes and has oncogenic potential.
  Oncogene, 26, 1769-1779.  
17279629 I.S.Chan, A.V.Fedorova, and J.A.Shin (2007).
The GCN4 bZIP targets noncognate gene regulatory sequences: quantitative investigation of binding at full and half sites.
  Biochemistry, 46, 1663-1671.  
17411433 J.B.Pereira-Leal, E.D.Levy, C.Kamp, and S.A.Teichmann (2007).
Evolution of protein complexes by duplication of homomeric interactions.
  Genome Biol, 8, R51.  
17360518 L.Guo, A.Han, D.L.Bates, J.Cao, and L.Chen (2007).
Crystal structure of a conserved N-terminal domain of histone deacetylase 4 reveals functional insights into glutamine-rich domains.
  Proc Natl Acad Sci U S A, 104, 4297-4302.
PDB codes: 2h8n 2o94
17148476 L.Ma, Y.Y.Sham, K.J.Walters, and H.C.Towle (2007).
A critical role for the loop region of the basic helix-loop-helix/leucine zipper protein Mlx in DNA binding and glucose-regulated transcription.
  Nucleic Acids Res, 35, 35-44.  
17314164 M.Shkreli, G.Dambrine, D.Soubieux, E.Kut, and D.Rasschaert (2007).
Involvement of the oncoprotein c-Myc in viral telomerase RNA gene regulation during Marek's disease virus-induced lymphomagenesis.
  J Virol, 81, 4848-4857.  
16475822 A.Banerjee, J.Hu, and D.J.Goss (2006).
Thermodynamics of protein-protein interactions of cMyc, Max, and Mad: effect of polyions on protein dimerization.
  Biochemistry, 45, 2333-2338.  
16520375 A.Chapman-Smith, and M.L.Whitelaw (2006).
Novel DNA binding by a basic helix-loop-helix protein. The role of the dioxin receptor PAS domain.
  J Biol Chem, 281, 12535-12545.  
16784907 A.V.Fedorova, I.S.Chan, and J.A.Shin (2006).
The GCN4 bZIP can bind to noncognate gene regulatory sequences.
  Biochim Biophys Acta, 1764, 1252-1259.  
16782875 C.L.Sans, D.J.Satterwhite, C.A.Stoltzman, K.T.Breen, and D.E.Ayer (2006).
MondoA-Mlx heterodimers are candidate sensors of cellular energy status: mitochondrial localization and direct regulation of glycolysis.
  Mol Cell Biol, 26, 4863-4871.  
16786196 C.Wang, G.Lee, W.Hsu, C.H.Yeh, M.L.Ho, and G.J.Wang (2006).
Identification of USF2 as a key regulator of Runx2 expression in mouse pluripotent mesenchymal D1 cells.
  Mol Cell Biochem, 292, 79-88.  
  19455201 M.Gerke, E.Bornberg-Bauer, X.Jiang, and G.Fuellen (2006).
Finding common protein interaction patterns across organisms.
  Evol Bioinform Online, 2, 45-52.  
16908182 P.J.Hurlin, and J.Huang (2006).
The MAX-interacting transcription factor network.
  Semin Cancer Biol, 16, 265-274.  
16705173 V.H.Cowling, S.Chandriani, M.L.Whitfield, and M.D.Cole (2006).
A conserved Myc protein domain, MBIV, regulates DNA binding, apoptosis, transformation, and G2 arrest.
  Mol Cell Biol, 26, 4226-4239.  
15593070 A.C.Beltran, P.E.Dawson, and J.M.Gottesfeld (2005).
Role of DNA sequence in the binding specificity of synthetic basic-helix-loop-helix domains.
  Chembiochem, 6, 104-113.  
15723054 C.Grandori, N.Gomez-Roman, Z.A.Felton-Edkins, C.Ngouenet, D.A.Galloway, R.N.Eisenman, and R.J.White (2005).
c-Myc binds to human ribosomal DNA and stimulates transcription of rRNA genes by RNA polymerase I.
  Nat Cell Biol, 7, 311-318.  
16260616 D.Skowronska-Krawczyk, L.Matter-Sadzinski, M.Ballivet, and J.M.Matter (2005).
The basic domain of ATH5 mediates neuron-specific promoter activity during retina development.
  Mol Cell Biol, 25, 10029-10039.  
16093321 G.Perini, D.Diolaiti, A.Porro, and G.Della Valle (2005).
In vivo transcriptional regulation of N-Myc target genes is controlled by E-box methylation.
  Proc Natl Acad Sci U S A, 102, 12117-12122.  
16356863 H.C.Chang, K.Tan, J.Ouyang, E.Parisini, J.H.Liu, Y.Le, X.Wang, E.L.Reinherz, and J.H.Wang (2005).
Structural and mutational analyses of a CD8alphabeta heterodimer and comparison with the CD8alphaalpha homodimer.
  Immunity, 23, 661-671.
PDB code: 2atp
15821734 H.van Bokhoven, J.Celli, J.van Reeuwijk, T.Rinne, B.Glaudemans, E.van Beusekom, P.Rieu, R.A.Newbury-Ecob, C.Chiang, and H.G.Brunner (2005).
MYCN haploinsufficiency is associated with reduced brain size and intestinal atresias in Feingold syndrome.
  Nat Genet, 37, 465-467.  
16080230 R.J.Brea, M.Amorín, L.Castedo, and J.R.Granja (2005).
Methyl-blocked dimeric alpha,gamma-peptide nanotube segments: formation of a peptide heterodimer through backbone-backbone interactions.
  Angew Chem Int Ed Engl, 44, 5710-5713.  
16064138 S.Adhikary, and M.Eilers (2005).
Transcriptional regulation and transformation by Myc proteins.
  Nat Rev Mol Cell Biol, 6, 635-645.  
15880794 S.D.Kiewitz, and C.Cabrele (2005).
Synthesis and conformational properties of protein fragments based on the Id family of DNA-binding and cell-differentiation inhibitors.
  Biopolymers, 80, 762-774.  
15831447 T.Hulf, P.Bellosta, M.Furrer, D.Steiger, D.Svensson, A.Barbour, and P.Gallant (2005).
Whole-genome analysis reveals a strong positional bias of conserved dMyc-dependent E-boxes.
  Mol Cell Biol, 25, 3401-3410.  
15851686 W.R.Atchley, and A.D.Fernandes (2005).
Sequence signatures and the probabilistic identification of proteins in the Myc-Max-Mad network.
  Proc Natl Acad Sci U S A, 102, 6401-6406.  
16196502 Z.Zhang, M.Li, E.R.Rayburn, D.L.Hill, R.Zhang, and H.Wang (2005).
Oncogenes as novel targets for cancer therapy (part III): transcription factors.
  Am J Pharmacogenomics, 5, 327-338.  
14638687 A.Chapman-Smith, J.K.Lutwyche, and M.L.Whitelaw (2004).
Contribution of the Per/Arnt/Sim (PAS) domains to DNA binding by the basic helix-loop-helix PAS transcriptional regulators.
  J Biol Chem, 279, 5353-5362.  
15121849 A.V.Grinberg, C.D.Hu, and T.K.Kerppola (2004).
Visualization of Myc/Max/Mad family dimers and the competition for dimerization in living cells.
  Mol Cell Biol, 24, 4294-4308.  
15756464 B.Baminger, M.L.Ludwiczek, B.Hoffmann, G.Kontaxis, K.Bister, and R.Konrat (2004).
Backbone assignment of the dimerization and DNA-binding domain of the oncogenic transcription factor v-Myc in complex with its authentic binding partner Max.
  J Biomol NMR, 30, 361-362.  
14968135 G.D.Amoutzias, D.L.Robertson, S.G.Oliver, and E.Bornberg-Bauer (2004).
Convergent evolution of gene networks by single-gene duplications in higher eukaryotes.
  EMBO Rep, 5, 274-279.  
15190133 K.Kinoshita, Y.Kikuchi, Y.Sasakura, M.Suzuki, Y.Fujii-Kuriyama, and K.Sogawa (2004).
Altered DNA binding specificity of Arnt by selection of partner bHLH-PAS proteins.
  Nucleic Acids Res, 32, 3169-3179.  
15186484 S.Jones (2004).
An overview of the basic helix-loop-helix proteins.
  Genome Biol, 5, 226.  
15024060 S.M.Cowley, R.S.Kang, J.V.Frangioni, J.J.Yada, A.M.DeGrand, I.Radhakrishnan, and R.N.Eisenman (2004).
Functional analysis of the Mad1-mSin3A repressor-corepressor interaction reveals determinants of specificity, affinity, and transcriptional response.
  Mol Cell Biol, 24, 2698-2709.  
14702347 V.Rishi, J.Gal, D.Krylov, J.Fridriksson, M.S.Boysen, S.Mandrup, and C.Vinson (2004).
SREBP-1 dimerization specificity maps to both the helix-loop-helix and leucine zipper domains: use of a dominant negative.
  J Biol Chem, 279, 11863-11874.  
15047710 X.Le Guezennec, G.Vriend, and H.G.Stunnenberg (2004).
Molecular determinants of the interaction of Mad with the PAH2 domain of mSin3.
  J Biol Chem, 279, 25823-25829.  
14749374 Z.Huang, J.A.Traugh, and J.M.Bishop (2004).
Negative control of the Myc protein by the stress-responsive kinase Pak2.
  Mol Cell Biol, 24, 1582-1594.  
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.