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PDBsum entry 1fap
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Complex (isomerase/kinase) PDB id
1fap

 

 

 

 

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Contents
Protein chains
107 a.a. *
95 a.a. *
Ligands
RAP
Waters ×69
* Residue conservation analysis
PDB id:
1fap
Name: Complex (isomerase/kinase)
Title: The structure of the immunophilin-immunosuppressant fkbp12-rapamycin complex interacting with human frap
Structure: Fk506-binding protein. Chain: a. Synonym: fkbp12. Engineered: yes. Frap. Chain: b. Fragment: frb. Synonym: fkbp-rapamycin associated protein. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Cell_line: bl21. Gene: human hippocampal cdna library. Expressed in: escherichia coli. Expression_system_taxid: 562. Palo alto, ca).
Biol. unit: Not given
Resolution:
2.70Å     R-factor:   0.193     R-free:   0.299
Authors: J.Choi,J.Chen,S.L.Schreiber,J.Clardy
Key ref: J.Choi et al. (1996). Structure of the FKBP12-rapamycin complex interacting with the binding domain of human FRAP. Science, 273, 239-242. PubMed id: 8662507 DOI: 10.1126/science.273.5272.239
Date:
15-Mar-96     Release date:   23-Jul-97    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
P62942  (FKB1A_HUMAN) -  Peptidyl-prolyl cis-trans isomerase FKBP1A from Homo sapiens
Seq:
Struc: 		108 a.a.
107 a.a.
Protein chain
Pfam   ArchSchema ?
P42345  (MTOR_HUMAN) -  Serine/threonine-protein kinase mTOR from Homo sapiens
Seq:
Struc: 		 
Seq:
Struc: 		 
Seq:
Struc: 		 
Seq:
Struc: 		 
Seq:
Struc: 		 
Seq:
Struc: 		2549 a.a.
95 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class 2: Chain A: E.C.5.2.1.8  - peptidylprolyl isomerase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: [protein]-peptidylproline (omega=180) = [protein]-peptidylproline (omega=0)
Peptidylproline (omega=180)
 = peptidylproline (omega=0)
   Enzyme class 3: Chain B: E.C.2.7.11.1  - non-specific serine/threonine protein kinase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction:
1. L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP + H+
2. L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein] + ADP + H+
L-seryl-[protein]
 + ATP
 = O-phospho-L-seryl-[protein]
 + ADP
 + H(+)
L-threonyl-[protein]
 + ATP
 = O-phospho-L-threonyl-[protein]
 + ADP
 + H(+)
Note, where more than one E.C. class is given (as above), each may correspond to a different protein domain or, in the case of polyprotein precursors, to a different mature protein.
Molecule diagrams generated from .mol files obtained from the KEGG ftp site

 

 
    reference    
 
 
DOI no: 10.1126/science.273.5272.239 Science 273:239-242 (1996)
PubMed id: 8662507  
 
 
Structure of the FKBP12-rapamycin complex interacting with the binding domain of human FRAP.
J.Choi, J.Chen, S.L.Schreiber, J.Clardy.
 
  ABSTRACT  
 
Rapamycin, a potent immunosuppressive agent, binds two proteins: the FK506-binding protein (FKBP12) and the FKBP-rapamycin-associated protein (FRAP). A crystal structure of the ternary complex of human FKBP12, rapamycin, and the FKBP12-rapamycin-binding (FRB) domain of human FRAP at a resolution of 2.7 angstroms revealed the two proteins bound together as a result of the ability of rapamycin to occupy two different hydrophobic binding pockets simultaneously. The structure shows extensive interactions between rapamycin and both proteins, but fewer interactions between the proteins. The structure of the FRB domain of FRAP clarifies both rapamycin-independent and -dependent effects observed for mutants of FRAP and its homologs in the family of proteins related to the ataxia-telangiectasia mutant gene product, and it illustrates how a small cell-permeable molecule can mediate protein dimerization.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
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PDB codes: 3ori 3orm 3oro
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PDB code: 2npu
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Interfacial inhibition of macromolecular interactions: nature's paradigm for drug discovery.
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Features of selective kinase inhibitors.
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Specific binding to intracellular proteins determines arterial transport properties for rapamycin and paclitaxel.
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Therapeutic potential of target of rapamycin inhibitors.
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Lessons from natural molecules.
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Exposure-response relationships and drug interactions of sirolimus.
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Design and structure-based study of new potential FKBP12 inhibitors.
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PDB codes: 1j4h 1j4i
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Rapamycin inhibits GM-CSF-induced neutrophil migration.
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Regulating cell surface glycosylation by small molecule control of enzyme localization.
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The ATRs, ATMs, and TORs are giant HEAT repeat proteins.
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14690613 K.Stankunas, J.H.Bayle, J.E.Gestwicki, Y.M.Lin, T.J.Wandless, and G.R.Crabtree (2003).
Conditional protein alleles using knockin mice and a chemical inducer of dimerization.
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14654833 L.Renault, B.Guibert, and J.Cherfils (2003).
Structural snapshots of the mechanism and inhibition of a guanine nucleotide exchange factor.
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PDB codes: 1r8m 1r8q 1r8r 1r8s 1s9d
12606564 M.Würtele, C.Jelich-Ottmann, A.Wittinghofer, and C.Oecking (2003).
Structural view of a fungal toxin acting on a 14-3-3 regulatory complex.
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PDB codes: 1o9c 1o9d 1o9e 1o9f
12796477 P.Rajan, D.M.Panchision, L.F.Newell, and R.D.McKay (2003).
BMPs signal alternately through a SMAD or FRAP-STAT pathway to regulate fate choice in CNS stem cells.
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12768627 S.Schlatter, C.Senn, and M.Fussenegger (2003).
Modulation of translation-initiation in CHO-K1 cells by rapamycin-induced heterodimerization of engineered eIF4G fusion proteins.
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11983923 B.Menand, T.Desnos, L.Nussaume, F.Berger, D.Bouchez, C.Meyer, and C.Robaglia (2002).
Expression and disruption of the Arabidopsis TOR (target of rapamycin) gene.
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12080086 D.C.Fingar, S.Salama, C.Tsou, E.Harlow, and J.Blenis (2002).
Mammalian cell size is controlled by mTOR and its downstream targets S6K1 and 4EBP1/eIF4E.
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11854489 I.Harvey, P.Garneau, and J.Pelletier (2002).
Forced engagement of a RNA/protein complex by a chemical inducer of dimerization to modulate gene expression.
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11751578 P.J.Pereira, M.C.Vega, E.González-Rey, R.Fernández-Carazo, S.Macedo-Ribeiro, F.X.Gomis-Rüth, A.González, and M.Coll (2002).
Trypanosoma cruzi macrophage infectivity potentiator has a rotamase core and a highly exposed alpha-helix.
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PDB code: 1jvw
11904411 T.Wehrman, B.Kleaveland, J.H.Her, R.F.Balint, and H.M.Blau (2002).
Protein-protein interactions monitored in mammalian cells via complementation of beta -lactamase enzyme fragments.
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11600372 M.C.Cruz, A.L.Goldstein, J.Blankenship, M.Del Poeta, J.R.Perfect, J.H.McCusker, Y.L.Bennani, M.E.Cardenas, and J.Heitman (2001).
Rapamycin and less immunosuppressive analogs are toxic to Candida albicans and Cryptococcus neoformans via FKBP12-dependent inhibition of TOR.
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11604421 T.Lechler, G.A.Jonsdottir, S.K.Klee, D.Pellman, and R.Li (2001).
A two-tiered mechanism by which Cdc42 controls the localization and activation of an Arp2/3-activating motor complex in yeast.
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Partitioning the transcriptional program induced by rapamycin among the effectors of the Tor proteins.
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10713512 C.C.Deivanayagam, M.Carson, A.Thotakura, S.V.Narayana, and R.S.Chodavarapu (2000).
Structure of FKBP12.6 in complex with rapamycin.
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PDB code: 1c9h
11058892 M.T.Ivery (2000).
Immunophilins: switched on protein binding domains?
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11057898 T.Schmelzle, and M.N.Hall (2000).
TOR, a central controller of cell growth.
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Protein kinase activity and identification of a toxic effector domain of the target of rapamycin TOR proteins in yeast.
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10322127 F.G.Kuruvilla, and S.L.Schreiber (1999).
The PIK-related kinases intercept conventional signaling pathways.
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10318894 I.Remy, and S.W.Michnick (1999).
Clonal selection and in vivo quantitation of protein interactions with protein-fragment complementation assays.
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10089303 J.Liang, J.Choi, and J.Clardy (1999).
Refined structure of the FKBP12-rapamycin-FRB ternary complex at 2.2 A resolution.
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PDB codes: 1nsg 2fap 3fap 4fap
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Rapamycin antifungal action is mediated via conserved complexes with FKBP12 and TOR kinase homologs in Cryptococcus neoformans.
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Antifungal activities of antineoplastic agents: Saccharomyces cerevisiae as a model system to study drug action.
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Affinity modulation of small-molecule ligands by borrowing endogenous protein surfaces.
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Cleavage of the cyclohexyl-subunit of rapamycin results in loss of immunosuppressive activity.
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Oligomerization domain-directed reassembly of active dihydrofolate reductase from rationally designed fragments.
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Rapamune (RAPA, rapamycin, sirolimus): mechanism of action immunosuppressive effect results from blockade of signal transduction and inhibition of cell cycle progression.
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Monitoring protein-protein interactions in intact eukaryotic cells by beta-galactosidase complementation.
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Inducible gene expression and protein translocation using nontoxic ligands identified by a mammalian three-hybrid screen.
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Distinct repression of translation by wortmannin and rapamycin.
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8994877 B.L.Stoddard, and K.E.Flick (1996).
Calcineurin-immunosuppressor complexes.
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8994885 M.A.Navia (1996).
Protein-drug complexes important for immunoregulation and organ transplantation.
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A humanized system for pharmacologic control of gene expression.
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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.

 

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