Side-chain interactions form late and cooperatively in the binding reaction between disordered peptides and PDZ domains
Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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Side-chain interactions form late and cooperatively in the binding reaction between disordered peptides and PDZ domains. / Haq, S Raza; Chi, Celestine N; Bach, Anders; Dogan, Jakob; Engström, Åke; Hultqvist, Greta; Karlsson, O. Andreas; Lundström, Patrik; Montemiglio, Linda Celeste; Strømgaard, Kristian; Gianni, Stefano; Jemth, Per.
I: Journal of the American Chemical Society, Bind 134, Nr. 1, 01.2012, s. 599-605.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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T1 - Side-chain interactions form late and cooperatively in the binding reaction between disordered peptides and PDZ domains
AU - Haq, S Raza
AU - Chi, Celestine N
AU - Bach, Anders
AU - Dogan, Jakob
AU - Engström, Åke
AU - Hultqvist, Greta
AU - Karlsson, O. Andreas
AU - Lundström, Patrik
AU - Montemiglio, Linda Celeste
AU - Strømgaard, Kristian
AU - Gianni, Stefano
AU - Jemth, Per
PY - 2012/1
Y1 - 2012/1
N2 - Intrinsically disordered proteins are very common and mediate numerous protein-protein and protein-DNA interactions. While it is clear that these interactions are instrumental for the life of the mammalian cell, there is a paucity of data regarding their molecular binding mechanisms. We have here used short peptides as a model system for intrinsically disordered proteins. Linear free-energy relationships based on rate and equilibrium constants for the binding of these peptides to ordered target proteins, PDZ domains, demonstrate that native side-chain interactions form mainly after the rate-limiting barrier for binding, in a cooperative fashion. This finding suggests that these disordered peptides first form a weak encounter complex with non-native interactions. The data do not support the recent notion that the affinities of intrinsically disordered proteins towards their targets are generally governed by their association rate constants. Instead, we observe the opposite for peptide-PDZ interactions, namely that changes in Kd correlate with changes in koff.
AB - Intrinsically disordered proteins are very common and mediate numerous protein-protein and protein-DNA interactions. While it is clear that these interactions are instrumental for the life of the mammalian cell, there is a paucity of data regarding their molecular binding mechanisms. We have here used short peptides as a model system for intrinsically disordered proteins. Linear free-energy relationships based on rate and equilibrium constants for the binding of these peptides to ordered target proteins, PDZ domains, demonstrate that native side-chain interactions form mainly after the rate-limiting barrier for binding, in a cooperative fashion. This finding suggests that these disordered peptides first form a weak encounter complex with non-native interactions. The data do not support the recent notion that the affinities of intrinsically disordered proteins towards their targets are generally governed by their association rate constants. Instead, we observe the opposite for peptide-PDZ interactions, namely that changes in Kd correlate with changes in koff.
KW - Former Faculty of Pharmaceutical Sciences
U2 - 10.1021/ja209341w
DO - 10.1021/ja209341w
M3 - Journal article
C2 - 22129097
VL - 134
SP - 599
EP - 605
JO - Journal of the American Chemical Society
JF - Journal of the American Chemical Society
SN - 0002-7863
IS - 1
ER -
ID: 35412490