PDBsum entry 1fgy

Go to PDB code: 
protein ligands links
Signaling protein PDB id
Protein chain
127 a.a. *
Waters ×136
* Residue conservation analysis
PDB id:
Name: Signaling protein
Title: Grp1 ph domain with ins(1,3,4,5)p4
Structure: Grp1. Chain: a. Fragment: pleckstrin homology domain (residues 261 - 387). Synonym: arf1 guanine nucleotide exchange factor and integrin binding protein homolog. Engineered: yes
Source: Mus musculus. House mouse. Organism_taxid: 10090. Expressed in: escherichia coli. Expression_system_taxid: 562
1.50Å     R-factor:   0.213     R-free:   0.247
Authors: S.E.Lietzke,S.Bose,T.Cronin,J.Klarlund,A.Chawla,M.P.Czech, D.G.Lambright
Key ref:
S.E.Lietzke et al. (2000). Structural basis of 3-phosphoinositide recognition by pleckstrin homology domains. Mol Cell, 6, 385-394. PubMed id: 10983985 DOI: 10.1016/S1097-2765(00)00038-1
29-Jul-00     Release date:   23-Aug-00    
Go to PROCHECK summary

Protein chain
Pfam   ArchSchema ?
O08967  (CYH3_MOUSE) -  Cytohesin-3
399 a.a.
127 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 1 residue position (black cross)


DOI no: 10.1016/S1097-2765(00)00038-1 Mol Cell 6:385-394 (2000)
PubMed id: 10983985  
Structural basis of 3-phosphoinositide recognition by pleckstrin homology domains.
S.E.Lietzke, S.Bose, T.Cronin, J.Klarlund, A.Chawla, M.P.Czech, D.G.Lambright.
Lipid second messengers generated by phosphoinositide (PI) 3-kinases regulate diverse cellular functions through interaction with pleckstrin homology (PH) domains in modular signaling proteins. The PH domain of Grp1, a PI 3-kinase-activated exchange factor for Arf GTPases, selectively binds phosphatidylinositol 3,4,5-trisphosphate with high affinity. We have determined the structure of the Grp1 PH domain in the unliganded form and bound to inositol 1,3,4,5-tetraphosphate. A novel mode of phosphoinositide recognition involving a 20-residue insertion within the beta6/beta7 loop explains the unusually high specificity of the Grp1 PH domain and the promiscuous 3-phosphoinositide binding typical of several PH domains including that of protein kinase B. When compared to other PH domains, general determinants of 3-phosphoinositide recognition and specificity can be deduced.
  Selected figure(s)  
Figure 5.
Figure 5. Localized Structural Changes Accompanying Head Group BindingOverlay of the unliganded (magenta) and Ins(1,3,4,5)P[4]-bound (cyan) forms of the Grp1 PH domain following superposition of Cα atoms.
Figure 6.
Figure 6. Comparison of Ins(1,3,4,5)P[4] Recognition by the Grp1 and Btk PH Domains(A) Space-filling representation with invariant residues of the signature motif shown in white and nonconserved residues from the three SDRs highlighted in green (β1/β2 loop), magenta (β3/β4 loop), and orange (hairpin insertion).(B) Schematic diagram showing direct interactions with the head group. Residues in the signature motif are indicated in blue.
  The above figures are reprinted by permission from Cell Press: Mol Cell (2000, 6, 385-394) copyright 2000.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
21222653 N.A.Gokhale, A.Zaremba, and S.B.Shears (2011).
Receptor-dependent compartmentalization of PPIP5K1, a kinase with a cryptic polyphosphoinositide binding domain.
  Biochem J, 434, 415-426.  
21310079 S.G.Jackson, S.Al-Saigh, C.Schultz, and M.S.Junop (2011).
Inositol pentakisphosphate isomers bind PH domains with varying specificity and inhibit phosphoinositide interactions.
  BMC Struct Biol, 11, 11.  
21041639 B.Miao, I.Skidan, J.Yang, A.Lugovskoy, M.Reibarkh, K.Long, T.Brazell, K.A.Durugkar, J.Maki, C.V.Ramana, B.Schaffhausen, G.Wagner, V.Torchilin, J.Yuan, and A.Degterev (2010).
Small molecule inhibition of phosphatidylinositol-3,4,5-triphosphate (PIP3) binding to pleckstrin homology domains.
  Proc Natl Acad Sci U S A, 107, 20126-20131.  
20669253 E.Kim (2010).
Insulin resistance at the crossroads of metabolic syndrome: systemic analysis using microarrays.
  Biotechnol J, 5, 919-929.  
20559318 T.G.Kutateladze (2010).
Translation of the phosphoinositide code by PI effectors.
  Nat Chem Biol, 6, 507-513.  
19654617 D.F.Ceccarelli, and F.Sicheri (2009).
Grb-ing hold of insulin signaling.
  Nat Struct Mol Biol, 16, 803-804.  
19666464 F.Campa, H.Y.Yoon, V.L.Ha, Z.Szentpetery, T.Balla, and P.A.Randazzo (2009).
A PH domain in the Arf GTPase-activating protein (GAP) ARAP1 binds phosphatidylinositol 3,4,5-trisphosphate and regulates Arf GAP activity independently of recruitment to the plasma membranes.
  J Biol Chem, 284, 28069-28083.  
19307184 I.Rodríguez-Escudero, A.Andrés-Pons, R.Pulido, M.Molina, and V.J.Cid (2009).
Phosphatidylinositol 3-Kinase-dependent Activation of Mammalian Protein Kinase B/Akt in Saccharomyces cerevisiae, an in Vivo Model for the Functional Study of Akt Mutations.
  J Biol Chem, 284, 13373-13383.  
19167305 J.D.Knight, and J.J.Falke (2009).
Single-molecule fluorescence studies of a PH domain: new insights into the membrane docking reaction.
  Biophys J, 96, 566-582.  
19648926 R.S.Depetris, J.Wu, and S.R.Hubbard (2009).
Structural and functional studies of the Ras-associating and pleckstrin-homology domains of Grb10 and Grb14.
  Nat Struct Mol Biol, 16, 833-839.
PDB code: 3hk0
19493313 S.V.Madhunapantula, and G.P.Robertson (2009).
The PTEN-AKT3 signaling cascade as a therapeutic target in melanoma.
  Pigment Cell Melanoma Res, 22, 400-419.  
19942142 V.Laketa, S.Zarbakhsh, E.Morbier, D.Subramanian, C.Dinkel, J.Brumbaugh, P.Zimmermann, R.Pepperkok, and C.Schultz (2009).
Membrane-permeant phosphoinositide derivatives as modulators of growth factor signaling and neurite outgrowth.
  Chem Biol, 16, 1190-1196.  
18523652 B.E.Steinberg, and S.Grinstein (2008).
Pathogen destruction versus intracellular survival: the role of lipids as phagosomal fate determinants.
  J Clin Invest, 118, 2002-2011.  
18490450 E.Macia, M.Partisani, C.Favard, E.Mortier, P.Zimmermann, M.F.Carlier, P.Gounon, F.Luton, and M.Franco (2008).
The pleckstrin homology domain of the Arf6-specific exchange factor EFA6 localizes to the plasma membrane by interacting with phosphatidylinositol 4,5-bisphosphate and F-actin.
  J Biol Chem, 283, 19836-19844.  
18469301 J.He, R.M.Haney, M.Vora, V.V.Verkhusha, R.V.Stahelin, and T.G.Kutateladze (2008).
Molecular mechanism of membrane targeting by the GRP1 PH domain.
  J Lipid Res, 49, 1807-1815.  
19026786 K.D.Swanson, Y.Tang, D.F.Ceccarelli, F.Poy, J.P.Sliwa, B.G.Neel, and M.J.Eck (2008).
The Skap-hom dimerization and PH domains comprise a 3'-phosphoinositide-gated molecular switch.
  Mol Cell, 32, 564-575.
PDB codes: 1u5g 2otx
18954143 K.E.Landgraf, C.Pilling, and J.J.Falke (2008).
Molecular mechanism of an oncogenic mutation that alters membrane targeting: Glu17Lys modifies the PIP lipid specificity of the AKT1 PH domain.
  Biochemistry, 47, 12260-12269.  
18550542 K.Hong, L.Lou, S.Gupta, F.Ribeiro-Neto, and D.L.Altschuler (2008).
A Novel Epac-Rap-PP2A Signaling Module Controls cAMP-dependent Akt Regulation.
  J Biol Chem, 283, 23129-23138.  
18471983 W.S.Park, W.D.Heo, J.H.Whalen, N.A.O'Rourke, H.M.Bryan, T.Meyer, and M.N.Teruel (2008).
Comprehensive identification of PIP3-regulated PH domains from C. elegans to H. sapiens by model prediction and live imaging.
  Mol Cell, 30, 381-392.  
18305032 Y.Yu, and J.C.Alwine (2008).
Interaction between simian virus 40 large T antigen and insulin receptor substrate 1 is disrupted by the K1 mutation, resulting in the loss of large T antigen-mediated phosphorylation of Akt.
  J Virol, 82, 4521-4526.  
17588168 A.Rosenhouse-Dantsker, and D.E.Logothetis (2007).
Molecular characteristics of phosphoinositide binding.
  Pflugers Arch, 455, 45-53.  
17984318 C.Frantz, A.Karydis, P.Nalbant, K.M.Hahn, and D.L.Barber (2007).
Positive feedback between Cdc42 activity and H+ efflux by the Na-H exchanger NHE1 for polarity of migrating cells.
  J Cell Biol, 179, 403-410.  
17339315 D.F.Ceccarelli, I.M.Blasutig, M.Goudreault, Z.Li, J.Ruston, T.Pawson, and F.Sicheri (2007).
Non-canonical interaction of phosphoinositides with pleckstrin homology domains of Tiam1 and ArhGAP9.
  J Biol Chem, 282, 13864-13874.
PDB codes: 2p0d 2p0f 2p0h
17823121 D.Manna, A.Albanese, W.S.Park, and W.Cho (2007).
Mechanistic basis of differential cellular responses of phosphatidylinositol 3,4-bisphosphate- and phosphatidylinositol 3,4,5-trisphosphate-binding pleckstrin homology domains.
  J Biol Chem, 282, 32093-32105.  
17277311 E.E.Kooijman, D.P.Tieleman, C.Testerink, T.Munnik, D.T.Rijkers, K.N.Burger, and Kruijff (2007).
An electrostatic/hydrogen bond switch as the basis for the specific interaction of phosphatidic acid with proteins.
  J Biol Chem, 282, 11356-11364.  
18042453 J.P.DiNitto, A.Delprato, M.T.Gabe Lee, T.C.Cronin, S.Huang, A.Guilherme, M.P.Czech, and D.G.Lambright (2007).
Structural basis and mechanism of autoregulation in 3-phosphoinositide-dependent Grp1 family Arf GTPase exchange factors.
  Mol Cell, 28, 569-583.
PDB codes: 2r09 2r0d
17825589 Y.Jia, K.K.Subramanian, C.Erneux, V.Pouillon, H.Hattori, H.Jo, J.You, D.Zhu, S.Schurmans, and H.R.Luo (2007).
Inositol 1,3,4,5-tetrakisphosphate negatively regulates phosphatidylinositol-3,4,5- trisphosphate signaling in neutrophils.
  Immunity, 27, 453-467.  
17167488 B.Fuss, T.Becker, I.Zinke, and M.Hoch (2006).
The cytohesin Steppke is essential for insulin signalling in Drosophila.
  Nature, 444, 945-948.  
16832691 F.J.Tamarkin, W.S.Kang, J.J.Cohen, M.A.Wheeler, and R.M.Weiss (2006).
A role for Akt in the rapid regulation of inflammatory and apoptotic pathways in mouse bladder.
  Naunyn Schmiedebergs Arch Pharmacol, 373, 349-359.  
16615893 H.Teo, D.J.Gill, J.Sun, O.Perisic, D.B.Veprintsev, Y.Vallis, S.D.Emr, and R.L.Williams (2006).
ESCRT-I core and ESCRT-II GLUE domain structures reveal role for GLUE in linking to ESCRT-I and membranes.
  Cell, 125, 99.
PDB codes: 2cay 2caz
16616874 J.H.Hurley (2006).
Membrane binding domains.
  Biochim Biophys Acta, 1761, 805-811.  
16500902 W.Wen, J.Yan, and M.Zhang (2006).
Structural characterization of the split pleckstrin homology domain in phospholipase C-gamma1 and its interaction with TRPC3.
  J Biol Chem, 281, 12060-12068.
PDB code: 2fjl
15698571 C.Edlich, G.Stier, B.Simon, M.Sattler, and C.Muhle-Goll (2005).
Structure and phosphatidylinositol-(3,4)-bisphosphate binding of the C-terminal PH domain of human pleckstrin.
  Structure, 13, 277-286.
PDB code: 1xx0
15986137 G.P.Robertson (2005).
Functional and therapeutic significance of Akt deregulation in malignant melanoma.
  Cancer Metastasis Rev, 24, 273-285.  
15784165 G.Song, G.Ouyang, and S.Bao (2005).
The activation of Akt/PKB signaling pathway and cell survival.
  J Cell Mol Med, 9, 59-71.  
16139503 J.G.Carlton, and P.J.Cullen (2005).
Coincidence detection in phosphoinositide signaling.
  Trends Cell Biol, 15, 540-547.  
16252003 J.Yan, W.Wen, W.Xu, J.F.Long, M.E.Adams, S.C.Froehner, and M.Zhang (2005).
Structure of the split PH domain and distinct lipid-binding properties of the PH-PDZ supramodule of alpha-syntrophin.
  EMBO J, 24, 3985-3995.
PDB codes: 1z86 1z87 2adz
15457207 D.Komander, A.Fairservice, M.Deak, G.S.Kular, A.R.Prescott, C.Peter Downes, S.T.Safrany, D.R.Alessi, and D.M.van Aalten (2004).
Structural insights into the regulation of PDK1 by phosphoinositides and inositol phosphates.
  EMBO J, 23, 3918-3928.
PDB codes: 1w1d 1w1g 1w1h
15199069 K.R.Skowronek, F.Guo, Y.Zheng, and N.Nassar (2004).
The C-terminal basic tail of RhoG assists the guanine nucleotide exchange factor trio in binding to phospholipids.
  J Biol Chem, 279, 37895-37907.
PDB code: 1nty
15249580 P.Mitra, Y.Zhang, L.E.Rameh, M.P.Ivshina, D.McCollum, J.J.Nunnari, G.M.Hendricks, M.L.Kerr, S.J.Field, L.C.Cantley, and A.H.Ross (2004).
A novel phosphatidylinositol(3,4,5)P3 pathway in fission yeast.
  J Cell Biol, 166, 205-211.  
15359279 T.C.Cronin, J.P.DiNitto, M.P.Czech, and D.G.Lambright (2004).
Structural determinants of phosphoinositide selectivity in splice variants of Grp1 family PH domains.
  EMBO J, 23, 3711-3720.
PDB codes: 1u27 1u29 1u2b
14612449 U.Roth, K.Curth, T.G.Unterman, and T.Kietzmann (2004).
The transcription factors HIF-1 and HNF-4 and the coactivator p300 are involved in insulin-regulated glucokinase gene expression via the phosphatidylinositol 3-kinase/protein kinase B pathway.
  J Biol Chem, 279, 2623-2631.  
12783873 A.H.Kim, T.Sasaki, and M.V.Chao (2003).
JNK-interacting protein 1 promotes Akt1 activation.
  J Biol Chem, 278, 29830-29836.  
12507995 C.Brock, M.Schaefer, H.P.Reusch, C.Czupalla, M.Michalke, K.Spicher, G.Schultz, and B.Nürnberg (2003).
Roles of G beta gamma in membrane recruitment and activation of p110 gamma/p101 phosphoinositide 3-kinase gamma.
  J Cell Biol, 160, 89-99.  
12885767 G.E.Cozier, D.Bouyoucef, and P.J.Cullen (2003).
Engineering the phosphoinositide-binding profile of a class I pleckstrin homology domain.
  J Biol Chem, 278, 39489-39496.  
  12694559 M.A.Lemmon (2003).
Phosphoinositide recognition domains.
  Traffic, 4, 201-213.  
12826668 M.Yun, L.Keshvara, C.G.Park, Y.M.Zhang, J.B.Dickerson, J.Zheng, C.O.Rock, T.Curran, and H.W.Park (2003).
Crystal structures of the Dab homology domains of mouse disabled 1 and 2.
  J Biol Chem, 278, 36572-36581.
PDB codes: 1m7e 1oqn 1p3r
12930993 S.M.Singh, and D.Murray (2003).
Molecular modeling of the membrane targeting of phospholipase C pleckstrin homology domains.
  Protein Sci, 12, 1934-1953.  
12670394 V.L.Tybulewicz, L.Ardouin, A.Prisco, and L.F.Reynolds (2003).
Vav1: a key signal transducer downstream of the TCR.
  Immunol Rev, 192, 42-52.  
12208851 D.A.Prober, and B.A.Edgar (2002).
Interactions between Ras1, dMyc, and dPI3K signaling in the developing Drosophila wing.
  Genes Dev, 16, 2286-2299.  
11809841 H.Nagaya, I.Wada, Y.J.Jia, and H.Kanoh (2002).
Diacylglycerol kinase delta suppresses ER-to-Golgi traffic via its SAM and PH domains.
  Mol Biol Cell, 13, 302-316.  
12120092 J.C.Reed (2002).
Apoptosis-based therapies.
  Nat Rev Drug Discov, 1, 111-121.  
11733501 J.Kunz, A.Fuelling, L.Kolbe, and R.A.Anderson (2002).
Stereo-specific substrate recognition by phosphatidylinositol phosphate kinases is swapped by changing a single amino acid residue.
  J Biol Chem, 277, 5611-5619.  
12228230 J.L.Zugaza, M.A.López-Lago, M.J.Caloca, M.Dosil, N.Movilla, and X.R.Bustelo (2002).
Structural determinants for the biological activity of Vav proteins.
  J Biol Chem, 277, 45377-45392.  
11889037 K.L.Rossman, D.K.Worthylake, J.T.Snyder, D.P.Siderovski, S.L.Campbell, and J.Sondek (2002).
A crystallographic view of interactions between Dbs and Cdc42: PH domain-assisted guanine nucleotide exchange.
  EMBO J, 21, 1315-1326.
PDB codes: 1kz7 1kzg
12052827 M.Mansour, S.Y.Lee, and B.Pohajdak (2002).
The N-terminal coiled coil domain of the cytohesin/ARNO family of guanine nucleotide exchange factors interacts with the scaffolding protein CASP.
  J Biol Chem, 277, 32302-32309.  
12094222 M.Turner, and D.D.Billadeau (2002).
VAV proteins as signal integrators for multi-subunit immune-recognition receptors.
  Nat Rev Immunol, 2, 476-486.  
12019260 P.Várnai, X.Lin, S.B.Lee, G.Tuymetova, T.Bondeva, A.Spät, S.G.Rhee, G.Hajnóczky, and T.Balla (2002).
Inositol lipid binding and membrane localization of isolated pleckstrin homology (PH) domains. Studies on the PH domains of phospholipase C delta 1 and p130.
  J Biol Chem, 277, 27412-27422.  
12105222 S.H.Lee, J.B.Jin, J.Song, M.K.Min, D.S.Park, Y.W.Kim, and I.Hwang (2002).
The intermolecular interaction between the PH domain and the C-terminal domain of Arabidopsis dynamin-like 6 determines lipid binding specificity.
  J Biol Chem, 277, 31842-31849.  
12021278 T.L.Shen, D.C.Han, and J.L.Guan (2002).
Association of Grb7 with phosphoinositides and its role in the regulation of cell migration.
  J Biol Chem, 277, 29069-29077.  
12177050 T.R.Palmby, K.Abe, and C.J.Der (2002).
Critical role of the pleckstrin homology and cysteine-rich domains in Vav signaling and transforming activity.
  J Biol Chem, 277, 39350-39359.  
12388557 Z.Nie, K.T.Stanley, S.Stauffer, K.M.Jacques, D.S.Hirsch, J.Takei, and P.A.Randazzo (2002).
AGAP1, an endosome-associated, phosphoinositide-dependent ADP-ribosylation factor GTPase-activating protein that affects actin cytoskeleton.
  J Biol Chem, 277, 48965-48975.  
11395417 B.Vanhaesebroeck, S.J.Leevers, K.Ahmadi, J.Timms, R.Katso, P.C.Driscoll, R.Woscholski, P.J.Parker, and M.D.Waterfield (2001).
Synthesis and function of 3-phosphorylated inositol lipids.
  Annu Rev Biochem, 70, 535-602.  
11684018 J.Bravo, D.Karathanassis, C.M.Pacold, M.E.Pacold, C.D.Ellson, K.E.Anderson, P.J.Butler, I.Lavenir, O.Perisic, P.T.Hawkins, L.Stephens, and R.L.Williams (2001).
The crystal structure of the PX domain from p40(phox) bound to phosphatidylinositol 3-phosphate.
  Mol Cell, 8, 829-839.
PDB code: 1h6h
11248547 J.H.Hurley, and T.Meyer (2001).
Subcellular targeting by membrane lipids.
  Curr Opin Cell Biol, 13, 146-152.  
11577097 J.T.Snyder, K.L.Rossman, M.A.Baumeister, W.M.Pruitt, D.P.Siderovski, C.J.Der, M.A.Lemmon, and J.Sondek (2001).
Quantitative analysis of the effect of phosphoinositide interactions on the function of Dbl family proteins.
  J Biol Chem, 276, 45868-45875.  
11295547 P.A.Randazzo, K.Miura, Z.Nie, A.Orr, A.B.Theibert, and B.G.Kearns (2001).
Cytohesins and centaurins: mediators of PI 3-kinase regulated Arf signaling.
  Trends Biochem Sci, 26, 220-221.  
11737823 S.Corvera (2001).
Phosphatidylinositol 3-kinase and the control of endosome dynamics: new players defined by structural motifs.
  Traffic, 2, 859-866.  
11230696 T.Kutateladze, and M.Overduin (2001).
Structural mechanism of endosome docking by the FYVE domain.
  Science, 291, 1793-1796.
PDB codes: 1hyi 1hyj
11555646 T.T.Ching, H.P.Lin, C.C.Yang, M.Oliveira, P.J.Lu, and C.S.Chen (2001).
Specific binding of the C-terminal Src homology 2 domain of the p85alpha subunit of phosphoinositide 3-kinase to phosphatidylinositol 3,4,5-trisphosphate. Localization and engineering of the phosphoinositide-binding motif.
  J Biol Chem, 276, 43932-43938.  
11114512 J.H.Hurley, Y.Tsujishita, and M.A.Pearson (2000).
Floundering about at cell membranes: a structural view of phospholipid signaling.
  Curr Opin Struct Biol, 10, 737-743.  
11114537 P.J.Cullen, and P.Chardin (2000).
Membrane targeting: what a difference a G makes.
  Curr Biol, 10, R876-R878.  
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.