Apr 5, 2007

The high-resolution NMR structure of the R21A Spc-SH3:P41 complex: understanding the determinants of binding affinity by comparison with Abl-SH3

BMC Structural Biology
Salvador CasaresFrancisco Conejero-Lara

Abstract

SH3 domains are small protein modules of 60-85 amino acids that bind to short proline-rich sequences with moderate-to-low affinity and specificity. Interactions with SH3 domains play a crucial role in regulation of many cellular processes (some are related to cancer and AIDS) and have thus been interesting targets in drug design. The decapeptide APSYSPPPPP (p41) binds with relatively high affinity to the SH3 domain of the Abl tyrosine kinase (Abl-SH3), while it has a 100 times lower affinity for the alpha-spectrin SH3 domain (Spc-SH3). Here we present the high-resolution structure of the complex between the R21A mutant of Spc-SH3 and p41 derived from NMR data. Thermodynamic parameters of binding of p41 to both WT and R21A Spc-SH3 were measured by a combination of isothermal titration and differential scanning calorimetry. Mutation of arginine 21 to alanine in Spc-SH3 increases 3- to 4-fold the binding affinity for p41 due to elimination at the binding-site interface of the steric clash produced by the longer arginine side chain. Amide hydrogen-deuterium experiments on the free and p41-bound R21A Spc-SH3 domain indicate that binding elicits a strong reduction in the conformational flexibility of the domain. Despite the great dif...Continue Reading

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References

Mentioned in this Paper

Arginine hydrochloride
Buffers
Thermodynamics
Muscle Rigidity
Fluctuation
NOESY
In Vivo NMR Spectroscopy
Covalent Interaction
Molecular Helix
Amides

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