PDBsum entry 2sem

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Signaling protein/inhibitor PDB id
Protein chains
58 a.a. *
Waters ×79
* Residue conservation analysis
PDB id:
Name: Signaling protein/inhibitor
Title: Sem5 sh3 domain complexed with peptoid inhibitor
Structure: Protein (sex muscle abnormal protein 5). Chain: a, b. Fragment: c-terminal sh3. Engineered: yes. Protein (sh3 peptoid inhibitor). Chain: c, d. Engineered: yes
Source: Caenorhabditis elegans. Organism_taxid: 6239. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008. Synthetic: yes. Other_details: peptidomimetic inhibitor
2.20Å     R-factor:   0.206     R-free:   0.279
Authors: J.T.Nguyen,C.W.Turck,F.E.Cohen,R.N.Zuckermann,W.A.Lim
Key ref:
J.T.Nguyen et al. (1998). Exploiting the basis of proline recognition by SH3 and WW domains: design of N-substituted inhibitors. Science, 282, 2088-2092. PubMed id: 9851931 DOI: 10.1126/science.282.5396.2088
02-Nov-98     Release date:   06-Jan-99    
Go to PROCHECK summary

Protein chains
Pfam   ArchSchema ?
P29355  (SEM5_CAEEL) -  Sex muscle abnormal protein 5
228 a.a.
58 a.a.
Key:    PfamA domain  Secondary structure  CATH domain


DOI no: 10.1126/science.282.5396.2088 Science 282:2088-2092 (1998)
PubMed id: 9851931  
Exploiting the basis of proline recognition by SH3 and WW domains: design of N-substituted inhibitors.
J.T.Nguyen, C.W.Turck, F.E.Cohen, R.N.Zuckermann, W.A.Lim.
Src homology 3 (SH3) and WW protein interaction domains bind specific proline-rich sequences. However, instead of recognizing critical prolines on the basis of side chain shape or rigidity, these domains broadly accepted amide N-substituted residues. Proline is apparently specifically selected in vivo, despite low complementarity, because it is the only endogenous N-substituted amino acid. This discriminatory mechanism explains how these domains achieve specific but low-affinity recognition, a property that is necessary for transient signaling interactions. The mechanism can be exploited: screening a series of ligands in which key prolines were replaced by nonnatural N-substituted residues yielded a ligand that selectively bound the Grb2 SH3 domain with 100 times greater affinity.
  Selected figure(s)  
Figure 1.
Fig. 1. Backbone substitution requirements for SH3 and WW domain recognition. (A) Structural mapping of alanine and sarcosine scanning results (Table 1). Peptide/domain complex interfaces (8, 9) shown schematically. Ligands adopt a PPII conformation, depicted schematically as a triangular prism. Residue positions (spheres) are color-coded by class: white--does not require either C^ - or N-substitution (alanine and sarcosine tolerant); green--requires C^ -substitution (alanine tolerant, sarcosine intolerant); orange--requires N-substitution (sarcosine tolerant, alanine intolerant). (B) Minimally sufficient recognition unit for SH3 and WW domain binding grooves. Schematic view of a single binding groove cross-section, looking down the PPII helical axis (viewed from left side of Fig. 1A). Minimally required atoms defined in this study, a sequential pair of C^ - and N-substituted residues, are solid black. The van der Waals binding surface that these atoms present is shaded. (C) Distinct mechanisms of proline recognition. Proline can be recognized by a lock and key mechanism, utilizing the full chemical potential of the side chain. In contrast, SH3 and WW domains recognized key prolines based on N-substitution. This mechanism utilizes relatively little of the binding potential of ligand or protein (hatched surface) but is still highly discriminatory for proline among natural amino acids.
Figure 3.
Fig. 3. Structural basis of peptoid recognition. (A) Structure of wild-type Sos peptide (PPPVPPRRR) bound to Crk SH3 domain (20). Proline-rich core binding grooves are indicated by dashed boxes. Highly conserved surface residues among the four SH3 domains studied here (one or two conservative amino acid types) are green. Variable surface residues (3+ amino acid types) are brown. The ligand PXXP core binds at the most conserved surface on the protein. (B) Structure of peptide 34 bound to Crk SH3 domain. N-(S)-1-Phenylethyl peptoid side chain (orange) bound at site P[2]. Close-up view from the same perspective as above. (C) Structure of peptide 39 bound to the Sem5 SH3 domain. N-Cyclopropylmethyl peptoid side chain (orange) bound at site P[ 1]. Close-up view from the same perspective as above.
  The above figures are reprinted by permission from the AAAs: Science (1998, 282, 2088-2092) copyright 1998.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

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PDB code: 2kxc
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Enteropathogenic Escherichia coli Tir is an SH2/3 ligand that recruits and activates tyrosine kinases required for pedestal formation.
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PDB codes: 2ho2 2idh 2oei
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PDB codes: 2jm8 2jm9 2jma
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Synthetic ligands discovered by in vitro selection.
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Ribosomal protein L10 interacts with the SH3 domain and regulates GDNF-induced neurite growth in SH-SY-5y cells.
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Recognition of Proline-Rich Motifs by Protein-Protein-Interaction Domains.
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15999186 S.Inglis, R.Jones, D.Fritz, C.Stojkoski, G.Booker, and S.Pyke (2005).
Synthesis of 5-, 6- and 7-substituted-2-aminoquinolines as SH3 domain ligands.
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Encodamers: unnatural peptide oligomers encoded in RNA.
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Structure of a gametocyte protein essential for sexual development in Plasmodium falciparum.
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PDB code: 1n81
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PDB code: 1h3h
12688310 S.M.Feller, G.Tuchscherer, and J.Voss (2003).
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Topography for independent binding of alpha-helical and PPII-helical ligands to a peroxisomal SH3 domain.
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PDB codes: 1jqq 1n5z
11857638 B.J.McFarland, and C.Beeson (2002).
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Diverse recognition of non-PxxP peptide ligands by the SH3 domains from p67(phox), Grb2 and Pex13p.
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PDB code: 1k4u
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Structure of the Tsg101 UEV domain in complex with the PTAP motif of the HIV-1 p6 protein.
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PDB codes: 1m4p 1m4q
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Characterization of a phosphorylated peptide and peptoid and peptoid-peptide hybrids by mass spectrometry.
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Protein-protein interfaces: mimics and inhibitors.
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Structure of the SH3-guanylate kinase module from PSD-95 suggests a mechanism for regulated assembly of MAGUK scaffolding proteins.
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PDB code: 1kjw
11395416 C.M.Pickart (2001).
Mechanisms underlying ubiquitination.
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Targeting Molecular Recognition: Exploring the Dual Role of Functional Pseudoprolines in the Design of SH3 Ligands This work was supported by the Swiss National Science Foundation.
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Localization of the Rsp5p ubiquitin-protein ligase at multiple sites within the endocytic pathway.
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11701327 H.Reiersen, and A.R.Rees (2001).
The hunchback and its neighbours: proline as an environmental modulator.
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11316885 K.V.Kishan, M.E.Newcomer, T.H.Rhodes, and S.D.Guilliot (2001).
Effect of pH and salt bridges on structural assembly: molecular structures of the monomer and intertwined dimer of the Eps8 SH3 domain.
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PDB codes: 1i07 1i0c
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Novel recognition mode between Vav and Grb2 SH3 domains.
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PDB codes: 1gcp 1gcq
11682324 M.Vidal, V.Gigoux, and C.Garbay (2001).
SH2 and SH3 domains as targets for anti-proliferative agents.
  Crit Rev Oncol Hematol, 40, 175-186.  
11828442 R.Ruijtenbeek, J.A.Kruijtzer, W.van de Wiel, M.J.Fischer, M.Flück, F.A.Redegeld, R.M.Liskamp, and F.P.Nijkamp (2001).
Peptoid - peptide hybrids that bind Syk SH2 domains involved in signal transduction.
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Fitting peptides into the RNA world.
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Antagonists of protein-protein interactions.
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Conversion of a T cell antagonist into an agonist by repairing a defect in the TCR/peptide/MHC interface: implications for TCR signaling.
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Inhibitors of Ras signal transduction as antitumor agents.
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Human alpha-fetoprotein peptides bind estrogen receptor and estradiol, and suppress breast cancer.
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10919999 J.Kolafa, J.W.Perram, and R.P.Bywater (2000).
Essential motions and energetic contributions of individual residues in a peptide bound to an SH3 domain.
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Evolution of binding affinity in a WW domain probed by phage display.
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Regulators of G protein signaling: a bestiary of modular protein binding domains.
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Ligand recognition by SH3 and WW domains: the role of N-alkylation in PPII helices.
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Characterization of novel antimicrobial peptoids.
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Structure of the enabled/VASP homology 1 domain-peptide complex: a key component in the spatial control of actin assembly.
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PDB code: 1evh
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