1nlo Citations

Molecular basis for the binding of SH3 ligands with non-peptide elements identified by combinatorial synthesis.

Chem. Biol. 3 661-70 (1996)
Cited: 22 times
EuropePMC logo PMID: 8807900



Protein-structure-based combinatorial chemistry has recently been used to discover several ligands containing non-peptide binding elements to the Src SH3 domain. The encoded library used has the form Cap-M1-M2-M3-PLPPLP, in which the Cap and Mi's are composed of a diverse set of organic monomers. The PLPPLP portion provided a structural bias directing the non-peptide fragment Cap-M1-M2-M3 to the SH3 specificity pocket. Fifteen ligands were selected from > 1.1 million distinct compounds. The structural basis for selection was unknown.


The solution structures of the Src SH3 domain complexed with two ligands containing non-peptide elements selected from the library were determined by multidimensional NMR spectroscopy. The non-peptide moieties of the ligands interact with the specificity pocket of Src SH3 domain differently from peptides complexed with SH3 domains. Structural information about the ligands was used to design various homologs, whose affinities for the SH3 domain were measured. The results provide a structural basis for understanding the selection of a few optimal ligands from a large library.


The cycle of protein-structure-based combinatorial chemistry followed by structure determination of the few highest affinity ligands provides a powerful new tool for the field of molecular recognition.

Articles - 1nlo mentioned but not cited (2)

  1. Direct molecular dynamics observation of protein folding transition state ensemble. Ding F, Dokholyan NV, Buldyrev SV, Stanley HE, Shakhnovich EI. Biophys. J. 83 3525-3532 (2002)
  2. Macromolecular crowding induces polypeptide compaction and decreases folding cooperativity. Tsao D, Dokholyan NV. Phys Chem Chem Phys 12 3491-3500 (2010)

Reviews citing this publication (7)

  1. Recognition of proline-rich motifs by protein-protein-interaction domains. Ball LJ, Kühne R, Schneider-Mergener J, Oschkinat H. Angew. Chem. Int. Ed. Engl. 44 2852-2869 (2005)
  2. SH2 and SH3 domains as targets for anti-proliferative agents. Vidal M, Gigoux V, Garbay C. Crit. Rev. Oncol. Hematol. 40 175-186 (2001)
  3. Library design concepts and implementation strategies. Hobbs DW, Guo T. J. Recept. Signal Transduct. Res. 21 311-356 (2001)
  4. Development of HIV entry inhibitors targeted to the coiled-coil regions of gp41. Jiang S, Debnath AK. Biochem. Biophys. Res. Commun. 269 641-646 (2000)
  5. Ligand recognition by SH3 and WW domains: the role of N-alkylation in PPII helices. Aghazadeh B, Rosen MK. Chem. Biol. 6 R241-6 (1999)
  6. Can drugs be designed? Hubbard RE. Curr. Opin. Biotechnol. 8 696-700 (1997)
  7. SH3 domains and drug design: ligands, structure, and biological function. Dalgarno DC, Botfield MC, Rickles RJ. Biopolymers 43 383-400 (1997)

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  1. Diffusion, crowding & protein stability in a dynamic molecular model of the bacterial cytoplasm. McGuffee SR, Elcock AH. PLoS Comput. Biol. 6 e1000694 (2010)
  2. Emergence of protein fold families through rational design. Ding F, Dokholyan NV. PLoS Comput. Biol. 2 e85 (2006)
  3. Improving SH3 domain ligand selectivity using a non-natural scaffold. Nguyen JT, Porter M, Amoui M, Miller WT, Zuckermann RN, Lim WA. Chem. Biol. 7 463-473 (2000)
  4. Reconstruction of ancestral protein sequences and its applications. Cai W, Pei J, Grishin NV. BMC Evol. Biol. 4 33 (2004)
  5. Topological determinants of protein domain swapping. Ding F, Prutzman KC, Campbell SL, Dokholyan NV. Structure 14 5-14 (2006)
  6. Herpesvirus ateles gene product Tio interacts with nonreceptor protein tyrosine kinases. Albrecht JC, Friedrich U, Kardinal C, Koehn J, Fleckenstein B, Feller SM, Biesinger B. J. Virol. 73 4631-4639 (1999)
  7. Crystallographic structure of the SH3 domain of the human c-Yes tyrosine kinase: loop flexibility and amyloid aggregation. Martín-García JM, Luque I, Mateo PL, Ruiz-Sanz J, Cámara-Artigas A. FEBS Lett. 581 1701-1706 (2007)
  8. Design and synthesis of SH3 domain binding ligands: modifications of the consensus sequence XPpXP. Witter DJ, Famiglietti SJ, Cambier JC, Castelhano AL. Bioorg. Med. Chem. Lett. 8 3137-3142 (1998)
  9. Acquisition of Fyn-selective SH3 domain ligands via a combinatorial library strategy. Li H, Lawrence DS. Chem. Biol. 12 905-912 (2005)
  10. SH3 domain of Bruton's tyrosine kinase can bind to proline-rich peptides of TH domain of the kinase and p120cbl. Patel HV, Tzeng SR, Liao CY, Chen SH, Cheng JW. Proteins 29 545-552 (1997)
  11. Competitively selected protein ligands pay their increase in specificity by a decrease in affinity. Hoffmann S, Funke SA, Wiesehan K, Moedder S, Glück JM, Feuerstein S, Gerdts M, Mötter J, Willbold D. Mol Biosyst 6 126-133 (2010)
  12. Improvement of structure-based potentials for protein folding by native and nonnative hydrogen bonds. Enciso M, Rey A. Biophys. J. 101 1474-1482 (2011)
  13. Reexamination of the recognition preference of the specificity pocket of the Abl SH3 domain. Santamaria F, Wu Z, Boulègue C, Pál G, Lu W. J. Mol. Recognit. 16 131-138 (2003)

Related citations provided by authors (5)

  1. Protein Structure-Based Combinatorial Chemistry: Discovery of Non-Peptide Binding Elements to Src SH3 Domain. Combs AP, Kapoor TM, Feng S, Chen JK, Daude-Snow LF, Schreiber SL J. Am. Chem. Soc. 118 287- (1996)
  2. Specific Interactions Outside the Proline-Rich Core of Two Classes of Src Homology 3 Ligands. Feng S, Kasahara C, Rickles RJ, Schreiber SL Proc. Natl. Acad. Sci. U.S.A. 92 12408- (1995)
  3. Structural Basis for the Binding of Proline-Rich Peptides to SH3 Domains. Yu H, Chen JK, Feng S, Dalgarno DC, Brauer AW, Schreiber SL Cell 76 933- (1994)
  4. Two Binding Orientations for Peptides to the Src SH3 Domain: Development of a General Model for SH3-Ligand Interactions. Feng S, Chen JK, Yu H, Simon JA, Schreiber SL Science 266 1241- (1994)
  5. Solution Structure of the SH3 Domain of Src and Identification of its Ligand-Binding Site. Yu H, Rosen MK, Shin TB, Seidel-Dugan C, Brugge JS, Schreiber SL Science 258 1665- (1992)