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PDBsum entry 1av5

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protein ligands Protein-protein interface(s) links
Protein kinase inhibitor PDB id
1av5
Jmol
Contents
Protein chain
113 a.a. *
Ligands
AP2
Waters ×120
* Residue conservation analysis
PDB id:
1av5
Name: Protein kinase inhibitor
Title: Pkci-substrate analog
Structure: Protein kinasE C interacting protein. Chain: a, b. Synonym: pkci-1, protein kinasE C inhibitor 1, hint protein, hit protein. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: hpkci-1. Expressed in: pichia pastoris. Expression_system_taxid: 4922.
Biol. unit: Dimer (from PDB file)
Resolution:
2.00Å     R-factor:   0.229     R-free:   0.279
Authors: C.D.Lima,M.G.Klein,W.A.Hendrickson
Key ref:
C.D.Lima et al. (1997). Structure-based analysis of catalysis and substrate definition in the HIT protein family. Science, 278, 286-290. PubMed id: 9323207 DOI: 10.1126/science.278.5336.286
Date:
25-Sep-97     Release date:   25-Mar-98    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam   ArchSchema ?
P49773  (HINT1_HUMAN) -  Histidine triad nucleotide-binding protein 1
Seq:
Struc:
126 a.a.
113 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     plasma membrane   6 terms 
  Biological process     signal transduction by p53 class mediator resulting in induction of apoptosis   6 terms 
  Biochemical function     catalytic activity     4 terms  

 

 
DOI no: 10.1126/science.278.5336.286 Science 278:286-290 (1997)
PubMed id: 9323207  
 
 
Structure-based analysis of catalysis and substrate definition in the HIT protein family.
C.D.Lima, M.G.Klein, W.A.Hendrickson.
 
  ABSTRACT  
 
The histidine triad (HIT) protein family is among the most ubiquitous and highly conserved in nature, but a biological activity has not yet been identified for any member of the HIT family. Fragile histidine triad protein (FHIT) and protein kinase C interacting protein (PKCI) were used in a structure-based approach to elucidate characteristics of in vivo ligands and reactions. Crystallographic structures of apo, substrate analog, pentacovalent transition-state analog, and product states of both enzymes reveal a catalytic mechanism and define substrate characteristics required for catalysis, thus unifying the HIT family as nucleotidyl hydrolases, transferases, or both. The approach described here may be useful in identifying structure-function relations between protein families identified through genomics.
 
  Selected figure(s)  
 
Figure 2.
Fig. 2. Stereo views of PKCI in (A) apo, (B) AMP-CP substrate analog, (C) adenosine-tungstate transition-state^ analog, and (D) AMP product-bound forms. The region shown was selected to highlight interactions between the ligand and^ protein residues surrounding one of the two equivalent ligand-binding sites in the HIT homodimer. A subset of residues is shown superimposed^ on the C backbone cardinal spline of each respective structure. Hydrogen bonds are denoted by dotted lines. The tryptophan shown is in the COOH-terminal tail of the other protomer. Figure generated^ with Setor (15).
Figure 3.
Fig. 3. Schematic diagram of FHIT in (A) apo, (B) AMP-CP substrate analog, (C) adenosine-tungstate transition-state^ analog, and (D) adenosine-sulfate product complexed forms. As in Fig. 2, hydrogen-bonding interactions are depicted by dotted^ lines. A subset of residues is shown superimposed on the C backbone^ cardinal spline of each respective structure.
 
  The above figures are reprinted by permission from the AAAs: Science (1997, 278, 286-290) copyright 1997.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
21316334 J.Martin, M.V.St-Pierre, and J.F.Dufour (2011).
Hit proteins, mitochondria and cancer.
  Biochim Biophys Acta, 1807, 626-632.  
21984210 P.Tumbale, C.D.Appel, R.Kraehenbuehl, P.D.Robertson, J.S.Williams, J.Krahn, I.Ahel, and R.S.Williams (2011).
Structure of an aprataxin-DNA complex with insights into AOA1 neurodegenerative disease.
  Nat Struct Mol Biol, 18, 1189-1195.
PDB code: 3szq
21984208 Y.Gong, D.Zhu, J.Ding, C.N.Dou, X.Ren, L.Gu, T.Jiang, and D.C.Wang (2011).
Crystal structures of aprataxin ortholog Hnt3 reveal the mechanism for reversal of 5'-adenylated DNA.
  Nat Struct Mol Biol, 18, 1297-1299.
PDB codes: 3sp4 3spd 3spl
21472612 Y.Li, R.Al-Eryani, M.L.Yarbrough, K.Orth, and H.L.Ball (2011).
Characterization of AMPylation on Threonine, Serine, and Tyrosine Using Mass Spectrometry.
  J Am Soc Mass Spectrom, 22, 752-761.  
20399182 N.Tanaka, P.Smith, and S.Shuman (2010).
Structure of the RNA 3'-phosphate cyclase-adenylate intermediate illuminates nucleotide specificity and covalent nucleotidyl transfer.
  Structure, 18, 449-457.
PDB code: 3kgd
19541768 H.Banerjee, J.B.Palenchar, M.Lukaszewicz, E.Bojarska, J.Stepinski, J.Jemielity, A.Guranowski, S.Ng, D.A.Wah, E.Darzynkiewicz, and V.Bellofatto (2009).
Identification of the HIT-45 protein from Trypanosoma brucei as an FHIT protein/dinucleoside triphosphatase: substrate specificity studies on the recombinant and endogenous proteins.
  RNA, 15, 1554-1564.  
19670211 R.Koike, A.Kidera, and M.Ota (2009).
Alteration of oligomeric state and domain architecture is essential for functional transformation between transferase and hydrolase with the same scaffold.
  Protein Sci, 18, 2060-2066.  
18430890 J.Kowalska, M.Lewdorowicz, J.Zuberek, E.Grudzien-Nogalska, E.Bojarska, J.Stepinski, R.E.Rhoads, E.Darzynkiewicz, R.E.Davis, and J.Jemielity (2008).
Synthesis and characterization of mRNA cap analogs containing phosphorothioate substitutions that bind tightly to eIF4E and are resistant to the decapping pyrophosphatase DcpS.
  RNA, 14, 1119-1131.  
18270824 Q.Liu, A.C.Puche, and J.B.Wang (2008).
Distribution and expression of protein kinase C interactive protein (PKCI/HINT1) in mouse central nervous system (CNS).
  Neurochem Res, 33, 1263-1276.  
17957392 S.A.Gabel, and R.E.London (2008).
Ternary borate-nucleoside complex stabilization by ribonuclease A demonstrates phosphate mimicry.
  J Biol Inorg Chem, 13, 207-217.  
18441014 S.W.Liu, V.Rajagopal, S.S.Patel, and M.Kiledjian (2008).
Mechanistic and kinetic analysis of the DcpS scavenger decapping enzyme.
  J Biol Chem, 283, 16427-16436.  
18836178 U.Rass, I.Ahel, and S.C.West (2008).
Molecular mechanism of DNA deadenylation by the neurological disease protein aprataxin.
  J Biol Chem, 283, 33994-34001.  
18398008 Z.Lu, D.Dunaway-Mariano, and K.N.Allen (2008).
The catalytic scaffold of the haloalkanoic acid dehalogenase enzyme superfamily acts as a mold for the trigonal bipyramidal transition state.
  Proc Natl Acad Sci U S A, 105, 5687-5692.
PDB codes: 2rar 2rav 2rb5 2rbk
17203012 E.Barbier, A.Zapata, E.Oh, Q.Liu, F.Zhu, A.Undie, T.Shippenberg, and J.B.Wang (2007).
Supersensitivity to amphetamine in protein kinase-C interacting protein/HINT1 knockout mice.
  Neuropsychopharmacology, 32, 1774-1782.  
17498066 I.Carmi, and E.Razin (2007).
The role played by key transcription factors in activated mast cells.
  Immunol Rev, 217, 280-291.  
18077326 J.Weiske, K.F.Albring, and O.Huber (2007).
The tumor suppressor Fhit acts as a repressor of beta-catenin transcriptional activity.
  Proc Natl Acad Sci U S A, 104, 20344-20349.  
17310323 J.Zawacka-Pankau, and A.J.Podhajska (2007).
Expression and simple, one-step purification of fragile histidine triad (Fhit) tumor suppressor mutant forms in Escherichia coli and their interaction with protoporphyrin IX.
  Biotechnol Lett, 29, 877-883.  
17804496 M.Kumar, H.Jayaram, R.Vasquez-Del Carpio, X.Jiang, Z.F.Taraporewala, R.H.Jacobson, J.T.Patton, and B.V.Prasad (2007).
Crystallographic and biochemical analysis of rotavirus NSP2 with nucleotides reveals a nucleoside diphosphate kinase-like activity.
  J Virol, 81, 12272-12284.
PDB codes: 2r7c 2r7j 2r7p 2r8f
17889645 U.Rass, I.Ahel, and S.C.West (2007).
Defective DNA repair and neurodegenerative disease.
  Cell, 130, 991.  
17419878 Y.Wei, J.Ko, L.F.Murga, and M.J.Ondrechen (2007).
Selective prediction of interaction sites in protein structures with THEMATICS.
  BMC Bioinformatics, 8, 119.  
16899489 A.D.van Dijk, and A.M.Bonvin (2006).
Solvated docking: introducing water into the modelling of biomolecular complexes.
  Bioinformatics, 22, 2340-2347.  
16186798 H.Li, Y.Zhang, T.Su, R.M.Santella, and I.B.Weinstein (2006).
Hint1 is a haplo-insufficient tumor suppressor in mice.
  Oncogene, 25, 713-721.  
16964241 I.Ahel, U.Rass, S.F.El-Khamisy, S.Katyal, P.M.Clements, P.J.McKinnon, K.W.Caldecott, and S.C.West (2006).
The neurodegenerative disease protein aprataxin resolves abortive DNA ligation intermediates.
  Nature, 443, 713-716.  
16762638 J.Martin, F.Magnino, K.Schmidt, A.C.Piguet, J.S.Lee, D.Semela, M.V.St-Pierre, A.Ziemiecki, D.Cassio, C.Brenner, S.S.Thorgeirsson, and J.F.Dufour (2006).
Hint2, a mitochondrial apoptotic sensitizer down-regulated in hepatocellular carcinoma.
  Gastroenterology, 130, 2179-2188.  
17174896 Q.Liu, J.C.Greimann, and C.D.Lima (2006).
Reconstitution, activities, and structure of the eukaryotic RNA exosome.
  Cell, 127, 1223-1237.
PDB code: 2nn6
16934294 R.Vasquez-Del Carpio, F.D.Gonzalez-Nilo, G.Riadi, Z.F.Taraporewala, and J.T.Patton (2006).
Histidine triad-like motif of the rotavirus NSP2 octamer mediates both RTPase and NTPase activities.
  J Mol Biol, 362, 539-554.  
  17142912 W.T.Lo, K.H.Chin, H.L.Shr, F.P.Gao, P.C.Lyu, A.H.Wang, and S.H.Chou (2006).
Crystallization and preliminary X-ray analysis of XC1015, a histidine triad-like protein from Xanthomonas campestris.
  Acta Crystallogr Sect F Struct Biol Cryst Commun, 62, 1263-1265.  
15856483 F.Rodier, R.P.Bahadur, P.Chakrabarti, and J.Janin (2005).
Hydration of protein-protein interfaces.
  Proteins, 60, 36-45.  
16001405 G.W.Han, R.Schwarzenbacher, D.McMullan, P.Abdubek, E.Ambing, H.Axelrod, T.Biorac, J.M.Canaves, H.J.Chiu, X.Dai, A.M.Deacon, M.DiDonato, M.A.Elsliger, A.Godzik, C.Grittini, S.K.Grzechnik, J.Hale, E.Hampton, J.Haugen, M.Hornsby, L.Jaroszewski, H.E.Klock, E.Koesema, A.Kreusch, P.Kuhn, S.A.Lesley, T.M.McPhillips, M.D.Miller, K.Moy, E.Nigoghossian, J.Paulsen, K.Quijano, R.Reyes, G.Spraggon, R.C.Stevens, H.van den Bedem, J.Velasquez, J.Vincent, A.White, G.Wolf, Q.Xu, K.O.Hodgson, J.Wooley, and I.A.Wilson (2005).
Crystal structure of an Apo mRNA decapping enzyme (DcpS) from Mouse at 1.83 A resolution.
  Proteins, 60, 797-802.
PDB code: 1vlr
16199869 Y.N.Lee, and E.Razin (2005).
Nonconventional involvement of LysRS in the molecular mechanism of USF2 transcriptional activity in FcepsilonRI-activated mast cells.
  Mol Cell Biol, 25, 8904-8912.  
14982931 A.Krakowiak, H.C.Pace, G.M.Blackburn, M.Adams, A.Mekhalfia, R.Kaczmarek, J.Baraniak, W.J.Stec, and C.Brenner (2004).
Biochemical, crystallographic, and mutagenic characterization of hint, the AMP-lysine hydrolase, with novel substrates and inhibitors.
  J Biol Chem, 279, 18711-18716.
PDB code: 1rzy
  15256063 B.Z.Yuan, A.M.Jefferson, N.C.Popescu, and S.H.Reynolds (2004).
Aberrant gene expression in human non small cell lung carcinoma cells exposed to demethylating agent 5-aza-2'-deoxycytidine.
  Neoplasia, 6, 412-419.  
15663001 J.V.Lehtonen, D.J.Still, V.V.Rantanen, J.Ekholm, D.Björklund, Z.Iftikhar, M.Huhtala, S.Repo, A.Jussila, J.Jaakkola, O.Pentikäinen, T.Nyrönen, T.Salminen, M.Gyllenberg, and M.S.Johnson (2004).
BODIL: a molecular modeling environment for structure-function analysis and drug design.
  J Comput Aided Mol Des, 18, 401-419.  
15507519 K.P.Parks, H.Seidle, N.Wright, J.B.Sperry, P.Bieganowski, K.Howitz, D.L.Wright, and C.Brenner (2004).
Altered specificity of Hint-W123Q supports a role for Hint inhibition by ASW in avian sex determination.
  Physiol Genomics, 20, 12-14.  
15273322 S.W.Liu, X.Jiao, H.Liu, M.Gu, C.D.Lima, and M.Kiledjian (2004).
Functional analysis of mRNA scavenger decapping enzymes.
  RNA, 10, 1412-1422.  
12824322 A.Stark, and R.B.Russell (2003).
Annotation in three dimensions. PINTS: Patterns in Non-homologous Tertiary Structures.
  Nucleic Acids Res, 31, 3341-3344.  
12867802 E.Koch, W.Fiedler, A.Tannapfel, and W.G.Ballhausen (2003).
Alteration of the fragile histidine triad gene in intrahepatic cholangiocarcinoma.
  Eur J Gastroenterol Hepatol, 15, 907-913.  
12574506 F.Trapasso, A.Krakowiak, R.Cesari, J.Arkles, S.Yendamuri, H.Ishii, A.Vecchione, T.Kuroki, P.Bieganowski, H.C.Pace, K.Huebner, C.M.Croce, and C.Brenner (2003).
Designed FHIT alleles establish that Fhit-induced apoptosis in cancer cells is limited by substrate binding.
  Proc Natl Acad Sci U S A, 100, 1592-1597.  
12524453 J.K.Yang, M.S.Park, G.S.Waldo, and S.W.Suh (2003).
Directed evolution approach to a structural genomics project: Rv2002 from Mycobacterium tuberculosis.
  Proc Natl Acad Sci U S A, 100, 455-460.
PDB codes: 1nff 1nfq 1nfr
12748294 N.Korsisaari, D.J.Rossi, K.Luukko, K.Huebner, M.Henkemeyer, and T.P.Mäkelä (2003).
The histidine triad protein Hint is not required for murine development or Cdk7 function.
  Mol Cell Biol, 23, 3929-3935.  
14638794 S.D.Reid, A.G.Montgomery, J.M.Voyich, F.R.DeLeo, B.Lei, R.M.Ireland, N.M.Green, M.Liu, S.Lukomski, and J.M.Musser (2003).
Characterization of an extracellular virulence factor made by group A Streptococcus with homology to the Listeria monocytogenes internalin family of proteins.
  Infect Immun, 71, 7043-7052.  
12810953 T.Su, M.Suzui, L.Wang, C.S.Lin, W.Q.Xing, and I.B.Weinstein (2003).
Deletion of histidine triad nucleotide-binding protein 1/PKC-interacting protein in mice enhances cell growth and carcinogenesis.
  Proc Natl Acad Sci U S A, 100, 7824-7829.  
12557261 T.Tsujiuchi, Y.Sasaki, T.Kubozoe, Y.Konishi, and M.Tsutsumi (2003).
Alterations in the Fhit gene in pancreatic duct adenocarcinomas induced by N-nitrosobis(2-oxopropyl)amine in hamsters.
  Mol Carcinog, 36, 60-66.  
12619037 T.Tsujiuchi, Y.Sasaki, Y.Oka, Y.Konishi, and M.Tsutsumi (2003).
Fhit gene alterations in hepatocarcinogenesis induced by a choline-deficient L-amino acid-defined diet in rats.
  Mol Carcinog, 36, 147-152.  
12119013 C.Brenner (2002).
Hint, Fhit, and GalT: function, structure, evolution, and mechanism of three branches of the histidine triad superfamily of nucleotide hydrolases and transferases.
  Biochemistry, 41, 9003-9014.  
12198172 H.Liu, N.D.Rodgers, X.Jiao, and M.Kiledjian (2002).
The scavenger mRNA decapping enzyme DcpS is a member of the HIT family of pyrophosphatases.
  EMBO J, 21, 4699-4708.  
11814598 M.Norin, and M.Sundström (2002).
Structural proteomics: developments in structure-to-function predictions.
  Trends Biotechnol, 20, 79-84.  
  12028594 M.Rubio-Texeira, J.M.Varnum, P.Bieganowski, and C.Brenner (2002).
Control of dinucleoside polyphosphates by the FHIT-homologous HNT2 gene, adenine biosynthesis and heat shock in Saccharomyces cerevisiae.
  BMC Mol Biol, 3, 7.  
11805111 P.Bieganowski, P.N.Garrison, S.C.Hodawadekar, G.Faye, L.D.Barnes, and C.Brenner (2002).
Adenosine monophosphoramidase activity of Hint and Hnt1 supports function of Kin28, Ccl1, and Tfb3.
  J Biol Chem, 277, 10852-10860.  
11877379 R.Lemaire, J.Prasad, T.Kashima, J.Gustafson, J.L.Manley, and R.Lafyatis (2002).
Stability of a PKCI-1-related mRNA is controlled by the splicing factor ASF/SF2: a novel function for SR proteins.
  Genes Dev, 16, 594-607.  
12112319 T.Tsujiuchi, Y.Sasaki, T.Kubozoe, M.Tsutsumi, Y.Konishi, and D.Nakae (2002).
Alterations of the Fhit gene in hepatocellular carcinomas induced by N-nitrosodiethylamine in rats.
  Mol Carcinog, 34, 19-24.  
11454219 A.Kitzerow, and B.Henrich (2001).
The cytosolic HinT protein of Mycoplasma hominis interacts with two membrane proteins.
  Mol Microbiol, 41, 279-287.  
11159990 J.E.Adamou, J.H.Heinrichs, A.L.Erwin, W.Walsh, T.Gayle, M.Dormitzer, R.Dagan, Y.A.Brewah, P.Barren, R.Lathigra, S.Langermann, S.Koenig, and S.Johnson (2001).
Identification and characterization of a novel family of pneumococcal proteins that are protective against sepsis.
  Infect Immun, 69, 949-958.  
  11701096 J.M.Varnum, J.Baraniak, R.Kaczmarek, W.J.Stec, and C.Brenner (2001).
Di-, tri- and tetra-5'-O-phosphorothioadenosyl substituted polyols as inhibitors of Fhit: Importance of the alpha-beta bridging oxygen and beta phosphorus replacement.
  BMC Chem Biol, 1, 3.  
11524683 J.Y.Lee, J.E.Kwak, J.Moon, S.H.Eom, E.C.Liong, J.D.Pedelacq, J.Berendzen, and S.W.Suh (2001).
Crystal structure and functional analysis of the SurE protein identify a novel phosphatase family.
  Nat Struct Biol, 8, 789-794.
PDB codes: 1j9j 1j9k 1j9l
11007992 A.G.McLennan (2000).
Dinucleoside polyphosphates-friend or foe?
  Pharmacol Ther, 87, 73-89.  
10673421 G.J.Palm, E.Billy, W.Filipowicz, and A.Wlodawer (2000).
Crystal structure of RNA 3'-terminal phosphate cyclase, a ubiquitous enzyme with unusual topology.
  Structure, 8, 13-23.
PDB codes: 1qmh 1qmi
10679341 L.Shapiro, and T.Harris (2000).
Finding function through structural genomics.
  Curr Opin Biotechnol, 11, 31-35.  
10903954 T.J.Boggon, and L.Shapiro (2000).
Screening for phasing atoms in protein crystallography.
  Structure, 8, R143-R149.  
10090754 A.Abend, P.N.Garrison, L.D.Barnes, and P.A.Frey (1999).
Stereochemical retention of the configuration in the action of Fhit on phosphorus-chiral substrates.
  Biochemistry, 38, 3668-3676.  
10407161 A.C.Asensio, S.Oaknin, and P.Rotllán (1999).
Fluorimetric detection of enzymatic activity associated with the human tumor suppressor Fhit protein.
  Biochim Biophys Acta, 1432, 396-400.  
10497298 C.Brenner, P.Bieganowski, H.C.Pace, and K.Huebner (1999).
The histidine triad superfamily of nucleotide-binding proteins.
  J Cell Physiol, 181, 179-187.  
10215898 E.A.Atencia, O.Madrid, M.A.Günther Sillero, and A.Sillero (1999).
T4 RNA ligase catalyzes the synthesis of dinucleoside polyphosphates.
  Eur J Biochem, 261, 802-811.  
  10595546 K.Volz (1999).
A test case for structure-based functional assignment: the 1.2 A crystal structure of the yjgF gene product from Escherichia coli.
  Protein Sci, 8, 2428-2437.
PDB code: 1qu9
9551548 B.Rost (1998).
Marrying structure and genomics.
  Structure, 6, 259-263.  
9685474 C.C.Zhang, L.Gonzalez, and V.Phalip (1998).
Survey, analysis and genetic organization of genes encoding eukaryotic-like signaling proteins on a cyanobacterial genome.
  Nucleic Acids Res, 26, 3619-3625.  
9576908 H.C.Pace, P.N.Garrison, A.K.Robinson, L.D.Barnes, A.Draganescu, A.Rösler, G.M.Blackburn, Z.Siprashvili, C.M.Croce, K.Huebner, and C.Brenner (1998).
Genetic, biochemical, and crystallographic characterization of Fhit-substrate complexes as the active signaling form of Fhit.
  Proc Natl Acad Sci U S A, 95, 5484-5489.
PDB codes: 1fhi 2fhi
9928473 K.Huebner, P.N.Garrison, L.D.Barnes, and C.M.Croce (1998).
The role of the FHIT/FRA3B locus in cancer.
  Annu Rev Genet, 32, 7.  
9666334 L.Holm (1998).
Unification of protein families.
  Curr Opin Struct Biol, 8, 372-379.  
9543008 C.Brenner, H.C.Pace, P.N.Garrison, A.K.Robinson, A.Rosler, X.H.Liu, G.M.Blackburn, C.M.Croce, K.Huebner, and L.D.Barnes (1997).
Purification and crystallization of complexes modeling the active state of the fragile histidine triad protein.
  Protein Eng, 10, 1461-1463.  
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.