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PDBsum entry 2sem

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protein ligands Protein-protein interface(s) links
Signaling protein/inhibitor PDB id
2sem
Jmol
Contents
Protein chains
58 a.a. *
Ligands
ACE-PRO-PRO-PRO-
VAL-IPG-PRO-ARG
ACE-PRO-PRO-PRO-
VAL-IPG-PRO-ARG-
ARG
Waters ×79
* Residue conservation analysis
PDB id:
2sem
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
Resolution:
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
Date:
02-Nov-98     Release date:   06-Jan-99    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam   ArchSchema ?
P29355  (SEM5_CAEEL) -  Sex muscle abnormal protein 5
Seq:
Struc:
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.
 
  ABSTRACT  
 
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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Human alpha-fetoprotein peptides bind estrogen receptor and estradiol, and suppress breast cancer.
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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 code is shown on the right.