PDBsum entry 1ukh

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Transferase PDB id
Jmol PyMol
Protein chain
321 a.a. *
Waters ×95
* Residue conservation analysis
PDB id:
Name: Transferase
Title: Structural basis for the selective inhibition of jnk1 by the scaffolding protein jip1 and sp600125
Structure: Mitogen-activated protein kinase 8 isoform 4. Chain: a. Fragment: residues 1-369. Synonym: jnk1. Engineered: yes. 11-mer peptide from c-jun-amino-terminal kinase interacting protein 1. Chain: b. Synonym: jip1.
Source: Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 562. Synthetic: yes. Other_details: this sequence occurs peptide synthesis
Biol. unit: Dimer (from PQS)
2.35Å     R-factor:   0.226     R-free:   0.245
Authors: Y.-S.Heo,Y.K.Kim,B.-J.Sung,H.S.Lee,J.I.Lee,C.I.Seo,S.- Y.Park,J.H.Kim,Y.-L.Hyun,Y.H.Jeon,S.Ro,T.G.Lee,J.M.Cho, K.Y.Hwang,C.-H.Yang
Key ref:
Y.S.Heo et al. (2004). Structural basis for the selective inhibition of JNK1 by the scaffolding protein JIP1 and SP600125. EMBO J, 23, 2185-2195. PubMed id: 15141161 DOI: 10.1038/sj.emboj.7600212
23-Aug-03     Release date:   30-Aug-04    
Go to PROCHECK summary

Protein chain
Pfam   ArchSchema ?
P45983  (MK08_HUMAN) -  Mitogen-activated protein kinase 8
427 a.a.
321 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 8 residue positions (black crosses)

 Enzyme reactions 
   Enzyme class: E.C.  - Mitogen-activated protein kinase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: ATP + a protein = ADP + a phosphoprotein
+ protein
+ phosphoprotein
Molecule diagrams generated from .mol files obtained from the KEGG ftp site
 Gene Ontology (GO) functional annotation 
  GO annot!
  Biological process     protein phosphorylation   1 term 
  Biochemical function     protein kinase activity     3 terms  


DOI no: 10.1038/sj.emboj.7600212 EMBO J 23:2185-2195 (2004)
PubMed id: 15141161  
Structural basis for the selective inhibition of JNK1 by the scaffolding protein JIP1 and SP600125.
Y.S.Heo, S.K.Kim, C.I.Seo, Y.K.Kim, B.J.Sung, H.S.Lee, J.I.Lee, S.Y.Park, J.H.Kim, K.Y.Hwang, Y.L.Hyun, Y.H.Jeon, S.Ro, J.M.Cho, T.G.Lee, C.H.Yang.
The c-jun N-terminal kinase (JNK) signaling pathway is regulated by JNK-interacting protein-1 (JIP1), which is a scaffolding protein assembling the components of the JNK cascade. Overexpression of JIP1 deactivates the JNK pathway selectively by cytoplasmic retention of JNK and thereby inhibits gene expression mediated by JNK, which occurs in the nucleus. Here, we report the crystal structure of human JNK1 complexed with pepJIP1, the peptide fragment of JIP1, revealing its selectivity for JNK1 over other MAPKs and the allosteric inhibition mechanism. The van der Waals contacts by the three residues (Pro157, Leu160, and Leu162) of pepJIP1 and the hydrogen bonding between Glu329 of JNK1 and Arg156 of pepJIP1 are critical for the selective binding. Binding of the peptide also induces a hinge motion between the N- and C-terminal domains of JNK1 and distorts the ATP-binding cleft, reducing the affinity of the kinase for ATP. In addition, we also determined the ternary complex structure of pepJIP1-bound JNK1 complexed with SP600125, an ATP-competitive inhibitor of JNK, providing the basis for the JNK specificity of the compound.
  Selected figure(s)  
Figure 4.
Figure 4 Distortion of the ATP-binding site caused by interdomain rearrangement upon pepJIP1 binding. (A) Structural comparison between JNK3 (green) and pepJIP1-bound JNK1 (violet) when the C-terminal domains of the kinases are superimposed. The conformational differences of the N-terminal domains can be easily distinguished when the conventional view of kinases is rotated by 45° along the horizontal axis. The yellow circle indicates the interaction between the 1 helix and the phosphorylation loop in JNK3, but not existing in JNK1 complexed with pepJIP1. (B) Comparison of ATP-binding sites between the JNK1 -pepJIP1 (violet) and JNK3 -AMPPNP (green) complexes. The AMPPNP bound in JNK3 is shown in a ball-and-stick model. The residues of JNK3 involved in the hydrogen bonding with AMPPNP are labeled. The side chains of the residues in the glycine-rich loop including E75 and A74 of JNK3 are omitted for clarity because the backbone amide groups only are involved in the hydrogen bonds with the phosphate groups of AMPPNP. (C) The structural comparison of the residues crucial for the catalytic activity between the JNK1 -pepJIP1 (violet) and JNK3 -AMPPNP (green) complexes. The residues in JNK1 and JNK3 are labeled red and black, respectively. In (B, C), hydrogen bonds are indicated by dashed lines.
Figure 5.
Figure 5 The inhibited phosphorylation of MBP, the docking site-independent substrate, due to the reduced ATP binding affinity to JNK1 by pepJIP1 binding. (A, B) The binding affinities of ATP to JNK1 were measured by ITC when pepJIP1 was unbound (A) and bound (B) to JNK1. (C) Dose-dependent inhibition of the kinase activity of JNK1 by pepJIP1 using MBP as substrates. The mutated pepJIP1 used for control experiment has the sequence of RPKAATTANAF.
  The above figures are reprinted from an Open Access publication published by Macmillan Publishers Ltd: EMBO J (2004, 23, 2185-2195) copyright 2004.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
21384452 A.F.Thévenin, C.L.Zony, B.J.Bahnson, and R.F.Colman (2011).
GSTpi modulates JNK activity through a direct interaction with JNK substrate, ATF2.
  Protein Sci, 20, 834-848.  
21162712 K.R.Ngoei, B.Catimel, N.Church, D.S.Lio, C.Dogovski, M.A.Perugini, P.M.Watt, H.C.Cheng, D.C.Ng, and M.A.Bogoyevitch (2011).
Characterization of a novel JNK (c-Jun N-terminal kinase) inhibitory peptide.
  Biochem J, 434, 399-413.  
21458276 S.K.De, E.Barile, V.Chen, J.L.Stebbins, J.F.Cellitti, T.Machleidt, C.B.Carlson, L.Yang, R.Dahl, and M.Pellecchia (2011).
Design, synthesis, and structure-activity relationship studies of thiophene-3-carboxamide derivatives as dual inhibitors of the c-Jun N-terminal kinase.
  Bioorg Med Chem, 19, 2582-2588.  
21494553 S.Lee, M.Warthaka, C.Yan, T.S.Kaoud, A.Piserchio, R.Ghose, P.Ren, and K.N.Dalby (2011).
A model of a MAPKā€¢substrate complex in an active conformation: a computational and experimental approach.
  PLoS One, 6, e18594.  
20878262 S.Mehan, H.Meena, D.Sharma, and R.Sankhla (2011).
JNK: A Stress-Activated Protein Kinase Therapeutic Strategies and Involvement in Alzheimer's and Various Neurodegenerative Abnormalities.
  J Mol Neurosci, 43, 376-390.  
21219631 S.R.Boston, R.Deshmukh, S.Strome, U.D.Priyakumar, A.D.MacKerell, and P.Shapiro (2011).
Characterization of ERK docking domain inhibitors that induce apoptosis by targeting Rsk-1 and caspase-9.
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19943845 C.Li, J.I.Macdonald, T.Hryciw, and S.O.Meakin (2010).
Nerve growth factor activation of the TrkA receptor induces cell death, by macropinocytosis, in medulloblastoma Daoy cells.
  J Neurochem, 112, 882-899.  
21134636 R.Akella, X.Min, Q.Wu, K.H.Gardner, and E.J.Goldsmith (2010).
The third conformation of p38Ī± MAP kinase observed in phosphorylated p38Ī± and in solution.
  Structure, 18, 1571-1578.
PDB code: 3p4k
20045647 S.K.De, V.Chen, J.L.Stebbins, L.H.Chen, J.F.Cellitti, T.Machleidt, E.Barile, M.Riel-Mehan, R.Dahl, L.Yang, A.Emdadi, R.Murphy, and M.Pellecchia (2010).
Synthesis and optimization of thiadiazole derivatives as a novel class of substrate competitive c-Jun N-terminal kinase inhibitors.
  Bioorg Med Chem, 18, 590-596.  
20510239 T.M.Lindstrom, and W.H.Robinson (2010).
A multitude of kinases--which are the best targets in treating rheumatoid arthritis?
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19196711 A.J.Bardwell, E.Frankson, and L.Bardwell (2009).
Selectivity of docking sites in MAPK kinases.
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19805511 A.W.Truman, K.Y.Kim, and D.E.Levin (2009).
Mechanism of Mpk1 mitogen-activated protein kinase binding to the Swi4 transcription factor and its regulation by a novel caffeine-induced phosphorylation.
  Mol Cell Biol, 29, 6449-6461.  
19591900 F.Chen, K.Beezhold, and V.Castranova (2009).
JNK1, a potential therapeutic target for hepatocellular carcinoma.
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19424502 M.C.Balasu, L.N.Spiridon, S.Miron, C.T.Craescu, A.J.Scheidig, A.J.Petrescu, and S.E.Szedlacsek (2009).
Interface analysis of the complex between ERK2 and PTP-SL.
  PLoS ONE, 4, e5432.  
19483709 M.Gaestel, A.Kotlyarov, and M.Kracht (2009).
Targeting innate immunity protein kinase signalling in inflammation.
  Nat Rev Drug Discov, 8, 480-499.  
19553156 M.R.Arkin, and A.Whitty (2009).
The road less traveled: modulating signal transduction enzymes by inhibiting their protein-protein interactions.
  Curr Opin Chem Biol, 13, 284-290.  
19393603 R.L.Zemans, and P.G.Arndt (2009).
Tec kinases regulate actin assembly and cytokine expression in LPS-stimulated human neutrophils via JNK activation.
  Cell Immunol, 258, 90-97.  
19271755 S.K.De, J.L.Stebbins, L.H.Chen, M.Riel-Mehan, T.Machleidt, R.Dahl, H.Yuan, A.Emdadi, E.Barile, V.Chen, R.Murphy, and M.Pellecchia (2009).
Design, synthesis, and structure-activity relationship of substrate competitive, selective, and in vivo active triazole and thiadiazole inhibitors of the c-Jun N-terminal kinase.
  J Med Chem, 52, 1943-1952.  
19282190 S.K.De, L.H.Chen, J.L.Stebbins, T.Machleidt, M.Riel-Mehan, R.Dahl, V.Chen, H.Yuan, E.Barile, A.Emdadi, R.Murphy, and M.Pellecchia (2009).
Discovery of 2-(5-nitrothiazol-2-ylthio)benzo[d]thiazoles as novel c-Jun N-terminal kinase inhibitors.
  Bioorg Med Chem, 17, 2712-2717.  
19243309 T.Chen, N.Kablaoui, J.Little, S.Timofeevski, W.R.Tschantz, P.Chen, J.Feng, M.Charlton, R.Stanton, and P.Bauer (2009).
Identification of small-molecule inhibitors of the JIP-JNK interaction.
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19261605 T.Kamenecka, J.Habel, D.Duckett, W.Chen, Y.Y.Ling, B.Frackowiak, R.Jiang, Y.Shin, X.Song, and P.Lograsso (2009).
Structure-Activity Relationships and X-ray Structures Describing the Selectivity of Aminopyrazole Inhibitors for c-Jun N-terminal Kinase 3 (JNK3) over p38.
  J Biol Chem, 284, 12853-12861.
PDB codes: 3fi2 3fi3
19141286 X.Min, R.Akella, H.He, J.M.Humphreys, S.E.Tsutakawa, S.J.Lee, J.A.Tainer, M.H.Cobb, and E.J.Goldsmith (2009).
The structure of the MAP2K MEK6 reveals an autoinhibitory dimer.
  Structure, 17, 96.
PDB code: 3enm
18408005 C.Guo, and A.J.Whitmarsh (2008).
The beta-arrestin-2 scaffold protein promotes c-Jun N-terminal kinase-3 activation by binding to its nonconserved N terminus.
  J Biol Chem, 283, 15903-15911.  
18287535 D.Dávila, and I.Torres-Aleman (2008).
Neuronal death by oxidative stress involves activation of FOXO3 through a two-arm pathway that activates stress kinases and attenuates insulin-like growth factor I signaling.
  Mol Biol Cell, 19, 2014-2025.  
18482985 D.L.Sheridan, Y.Kong, S.A.Parker, K.N.Dalby, and B.E.Turk (2008).
Substrate discrimination among mitogen-activated protein kinases through distinct docking sequence motifs.
  J Biol Chem, 283, 19511-19520.  
18922779 J.L.Stebbins, S.K.De, T.Machleidt, B.Becattini, J.Vazquez, C.Kuntzen, L.H.Chen, J.F.Cellitti, M.Riel-Mehan, A.Emdadi, G.Solinas, M.Karin, and M.Pellecchia (2008).
Identification of a new JNK inhibitor targeting the JNK-JIP interaction site.
  Proc Natl Acad Sci U S A, 105, 16809-16813.  
18494454 J.Vazquez, S.K.De, L.H.Chen, M.Riel-Mehan, A.Emdadi, J.Cellitti, J.L.Stebbins, M.F.Rega, and M.Pellecchia (2008).
Development of paramagnetic probes for molecular recognition studies in protein kinases.
  J Med Chem, 51, 3460-3465.  
18426980 J.Yamauchi, Y.Miyamoto, J.R.Chan, and A.Tanoue (2008).
ErbB2 directly activates the exchange factor Dock7 to promote Schwann cell migration.
  J Cell Biol, 181, 351-365.  
18480048 M.L.Chu, L.M.Chavas, K.T.Douglas, P.A.Eyers, and L.Tabernero (2008).
Crystal structure of the catalytic domain of the mitotic checkpoint kinase Mps1 in complex with SP600125.
  J Biol Chem, 283, 21495-21500.
PDB codes: 2zmc 2zmd
18068683 R.Akella, T.M.Moon, and E.J.Goldsmith (2008).
Unique MAP Kinase binding sites.
  Biochim Biophys Acta, 1784, 48-55.  
18545666 S.Galli, V.G.Antico Arciuch, C.Poderoso, D.P.Converso, Q.Zhou, E.Bal de Kier Joffé, E.Cadenas, J.Boczkowski, M.C.Carreras, and J.J.Poderoso (2008).
Tumor cell phenotype is sustained by selective MAPK oxidation in mitochondria.
  PLoS ONE, 3, e2379.  
18212044 Y.Murakami, K.Tatebayashi, and H.Saito (2008).
Two adjacent docking sites in the yeast Hog1 mitogen-activated protein (MAP) kinase differentially interact with the Pbs2 MAP kinase kinase and the Ptp2 protein tyrosine phosphatase.
  Mol Cell Biol, 28, 2481-2494.  
17496919 A.G.Turjanski, J.P.Vaqué, and J.S.Gutkind (2007).
MAP kinases and the control of nuclear events.
  Oncogene, 26, 3240-3253.  
17395714 A.White, C.A.Pargellis, J.M.Studts, B.G.Werneburg, and B.T.Farmer (2007).
Molecular basis of MAPK-activated protein kinase 2:p38 assembly.
  Proc Natl Acad Sci U S A, 104, 6353-6358.
PDB code: 2oza
17303404 C.R.Weston, and R.J.Davis (2007).
The JNK signal transduction pathway.
  Curr Opin Cell Biol, 19, 142-149.  
17937911 G.Bunkoczi, E.Salah, P.Filippakopoulos, O.Fedorov, S.Müller, F.Sobott, S.A.Parker, H.Zhang, W.Min, B.E.Turk, and S.Knapp (2007).
Structural and functional characterization of the human protein kinase ASK1.
  Structure, 15, 1215-1226.
PDB code: 2clq
17079291 H.J.Zapata, M.Nakatsugawa, and J.F.Moffat (2007).
Varicella-zoster virus infection of human fibroblast cells activates the c-Jun N-terminal kinase pathway.
  J Virol, 81, 977-990.  
17585314 J.A.Ubersax, and J.E.Ferrell (2007).
Mechanisms of specificity in protein phosphorylation.
  Nat Rev Mol Cell Biol, 8, 530-541.  
17496909 M.Raman, W.Chen, and M.H.Cobb (2007).
Differential regulation and properties of MAPKs.
  Oncogene, 26, 3100-3112.  
17658891 O.Abramczyk, M.A.Rainey, R.Barnes, L.Martin, and K.N.Dalby (2007).
Expanding the repertoire of an ERK2 recruitment site: cysteine footprinting identifies the D-recruitment site as a mediator of Ets-1 binding.
  Biochemistry, 46, 9174-9186.  
18060821 Y.Zhu, H.Li, C.Long, L.Hu, H.Xu, L.Liu, S.Chen, D.C.Wang, and F.Shao (2007).
Structural insights into the enzymatic mechanism of the pathogenic MAPK phosphothreonine lyase.
  Mol Cell, 28, 899-913.
PDB codes: 2p1w 2q8y
17079133 A.Reményi, M.C.Good, and W.A.Lim (2006).
Docking interactions in protein kinase and phosphatase networks.
  Curr Opin Struct Biol, 16, 676-685.  
17046812 B.Zhou, J.Zhang, S.Liu, S.Reddy, F.Wang, and Z.Y.Zhang (2006).
Mapping ERK2-MKP3 binding interfaces by hydrogen/deuterium exchange mass spectrometry.
  J Biol Chem, 281, 38834-38844.  
16533805 D.T.Ho, A.J.Bardwell, S.Grewal, C.Iverson, and L.Bardwell (2006).
Interacting JNK-docking sites in MKK7 promote binding and activation of JNK mitogen-activated protein kinases.
  J Biol Chem, 281, 13169-13179.  
16648477 H.Zhou, M.Zheng, J.Chen, C.Xie, A.R.Kolatkar, T.Zarubin, Z.Ye, R.Akella, S.Lin, E.J.Goldsmith, and J.Han (2006).
Determinants that control the specific interactions between TAB1 and p38alpha.
  Mol Cell Biol, 26, 3824-3834.  
16884917 L.Bardwell, and K.Shah (2006).
Analysis of mitogen-activated protein kinase activation and interactions with regulators and substrates.
  Methods, 40, 213-223.  
17052210 L.Bardwell (2006).
Mechanisms of MAPK signalling specificity.
  Biochem Soc Trans, 34, 837-841.  
17158707 M.A.Bogoyevitch, and B.Kobe (2006).
Uses for JNK: the many and varied substrates of the c-Jun N-terminal kinases.
  Microbiol Mol Biol Rev, 70, 1061-1095.  
16456539 O.Kristensen, S.Guenat, I.Dar, N.Allaman-Pillet, A.Abderrahmani, M.Ferdaoussi, R.Roduit, F.Maurer, J.S.Beckmann, J.S.Kastrup, M.Gajhede, and C.Bonny (2006).
A unique set of SH3-SH3 interactions controls IB1 homodimerization.
  EMBO J, 25, 785-797.
PDB codes: 2fpd 2fpe 2fpf
16756506 R.P.Bhattacharyya, A.Reményi, B.J.Yeh, and W.A.Lim (2006).
Domains, motifs, and scaffolds: the role of modular interactions in the evolution and wiring of cell signaling circuits.
  Annu Rev Biochem, 75, 655-680.  
16567630 S.Liu, J.P.Sun, B.Zhou, and Z.Y.Zhang (2006).
Structural basis of docking interactions between ERK2 and MAP kinase phosphatase 3.
  Proc Natl Acad Sci U S A, 103, 5326-5331.
PDB code: 2fys
16765894 T.Zhou, L.Sun, J.Humphreys, and E.J.Goldsmith (2006).
Docking interactions induce exposure of activation loop in the MAP kinase ERK2.
  Structure, 14, 1011-1019.
PDB code: 2gph
16809784 X.Shi-Wen, F.Rodríguez-Pascual, S.Lamas, A.Holmes, S.Howat, J.D.Pearson, M.R.Dashwood, R.M.du Bois, C.P.Denton, C.M.Black, D.J.Abraham, and A.Leask (2006).
Constitutive ALK5-independent c-Jun N-terminal kinase activation contributes to endothelin-1 overexpression in pulmonary fibrosis: evidence of an autocrine endothelin loop operating through the endothelin A and B receptors.
  Mol Cell Biol, 26, 5518-5527.  
17085044 Z.Shi, K.A.Resing, and N.G.Ahn (2006).
Networks for the allosteric control of protein kinases.
  Curr Opin Struct Biol, 16, 686-692.  
16364919 A.Reményi, M.C.Good, R.P.Bhattacharyya, and W.A.Lim (2005).
The role of docking interactions in mediating signaling input, output, and discrimination in the yeast MAPK network.
  Mol Cell, 20, 951-962.
PDB codes: 2b9f 2b9h 2b9i 2b9j
16148006 C.Tárrega, P.Ríos, R.Cejudo-Marín, C.Blanco-Aparicio, L.van den Berk, J.Schepens, W.Hendriks, L.Tabernero, and R.Pulido (2005).
ERK2 shows a restrictive and locally selective mechanism of recognition by its tyrosine phosphatase inactivators not shared by its activator MEK1.
  J Biol Chem, 280, 37885-37894.  
16246839 D.M.Molina, S.Grewal, and L.Bardwell (2005).
Characterization of an ERK-binding domain in microphthalmia-associated transcription factor and differential inhibition of ERK2-mediated substrate phosphorylation.
  J Biol Chem, 280, 42051-42060.  
15812788 D.Shin, Y.S.Heo, K.J.Lee, C.M.Kim, J.M.Yoon, J.I.Lee, Y.L.Hyun, Y.H.Jeon, T.G.Lee, J.M.Cho, and S.Ro (2005).
Structural chemoproteomics and drug discovery.
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15882611 M.A.Bogoyevitch (2005).
Therapeutic promise of JNK ATP-noncompetitive inhibitors.
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16113653 M.Schmidt, Y.Budirahardja, R.Klompmaker, and R.H.Medema (2005).
Ablation of the spindle assembly checkpoint by a compound targeting Mps1.
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16061178 P.López-Bergami, H.Habelhah, A.Bhoumik, W.Zhang, L.H.Wang, and Z.Ronai (2005).
RACK1 mediates activation of JNK by protein kinase C [corrected].
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15501728 L.Resnick, and M.Fennell (2004).
Targeting JNK3 for the treatment of neurodegenerative disorders.
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15208323 R.K.Barr, I.Boehm, P.V.Attwood, P.M.Watt, and M.A.Bogoyevitch (2004).
The critical features and the mechanism of inhibition of a kinase interaction motif-based peptide inhibitor of JNK.
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15271995 R.K.Barr, R.M.Hopkins, P.M.Watt, and M.A.Bogoyevitch (2004).
Reverse two-hybrid screening identifies residues of JNK required for interaction with the kinase interaction motif of JNK-interacting protein-1.
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15567863 R.Ricci, G.Sumara, I.Sumara, I.Rozenberg, M.Kurrer, A.Akhmedov, M.Hersberger, U.Eriksson, F.R.Eberli, B.Becher, J.Borén, M.Chen, M.I.Cybulsky, K.J.Moore, M.W.Freeman, E.F.Wagner, C.M.Matter, and T.F.Lüscher (2004).
Requirement of JNK2 for scavenger receptor A-mediated foam cell formation in atherogenesis.
  Science, 306, 1558-1561.  
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.