Energetic pathway sampling in a protein interaction domain

Greta Hultqvist; S. Raza Haq; Avinash S. Punekar; Celestine N. Chi; Ake Engström; Anders Bach; Kristian Strømgaard; Maria Selmer; Stefano Gianni; Per Jemth

doi:10.1016/j.str.2013.05.010

Energetic pathway sampling in a protein interaction domain

Greta Hultqvist, S. Raza Haq, Avinash S. Punekar, Celestine N. Chi, Ake Engström, Anders Bach, Kristian Strømgaard, Maria Selmer, Stefano Gianni, Per Jemth

Department of Drug Design and Pharmacology

30 Citations (Scopus)

Abstract

The affinity and specificity of protein-ligand interactions are influenced by energetic crosstalk within the protein domain. However, the molecular details of such intradomain allostery are still unclear. Here, we have experimentally detected and computationally predicted interaction pathways in the postsynaptic density 95/discs large/zonula occludens 1 (PDZ)-peptide ligand model system using wild-type and circularly permuted PDZ proteins. The circular permutant introduced small perturbations in the tertiary structure and a concomitant rewiring of allosteric pathways, allowing us to describe how subtle changes may reshape energetic signaling. The results were analyzed in the context of other members of the PDZ family, which were found to contain distinct interaction pathways for different peptide ligands. The data reveal a fascinating scenario whereby several energetic pathways are sampled within one single domain and distinct pathways are activated by specific protein ligands.

Original language	English
Journal	Structure
Volume	21
Issue number	7
Pages (from-to)	1193-1202
ISSN	0969-2126
DOIs	https://doi.org/10.1016/j.str.2013.05.010
Publication status	Published - 2 Jul 2013

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title = "Energetic pathway sampling in a protein interaction domain",

abstract = "The affinity and specificity of protein-ligand interactions are influenced by energetic crosstalk within the protein domain. However, the molecular details of such intradomain allostery are still unclear. Here, we have experimentally detected and computationally predicted interaction pathways in the postsynaptic density 95/discs large/zonula occludens 1 (PDZ)-peptide ligand model system using wild-type and circularly permuted PDZ proteins. The circular permutant introduced small perturbations in the tertiary structure and a concomitant rewiring of allosteric pathways, allowing us to describe how subtle changes may reshape energetic signaling. The results were analyzed in the context of other members of the PDZ family, which were found to contain distinct interaction pathways for different peptide ligands. The data reveal a fascinating scenario whereby several energetic pathways are sampled within one single domain and distinct pathways are activated by specific protein ligands.",

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AU - Hultqvist, Greta

AU - Haq, S. Raza

AU - Punekar, Avinash S.

AU - Chi, Celestine N.

AU - Engström, Ake

AU - Bach, Anders

AU - Strømgaard, Kristian

AU - Selmer, Maria

AU - Gianni, Stefano

AU - Jemth, Per

PY - 2013/7/2

Y1 - 2013/7/2

N2 - The affinity and specificity of protein-ligand interactions are influenced by energetic crosstalk within the protein domain. However, the molecular details of such intradomain allostery are still unclear. Here, we have experimentally detected and computationally predicted interaction pathways in the postsynaptic density 95/discs large/zonula occludens 1 (PDZ)-peptide ligand model system using wild-type and circularly permuted PDZ proteins. The circular permutant introduced small perturbations in the tertiary structure and a concomitant rewiring of allosteric pathways, allowing us to describe how subtle changes may reshape energetic signaling. The results were analyzed in the context of other members of the PDZ family, which were found to contain distinct interaction pathways for different peptide ligands. The data reveal a fascinating scenario whereby several energetic pathways are sampled within one single domain and distinct pathways are activated by specific protein ligands.

AB - The affinity and specificity of protein-ligand interactions are influenced by energetic crosstalk within the protein domain. However, the molecular details of such intradomain allostery are still unclear. Here, we have experimentally detected and computationally predicted interaction pathways in the postsynaptic density 95/discs large/zonula occludens 1 (PDZ)-peptide ligand model system using wild-type and circularly permuted PDZ proteins. The circular permutant introduced small perturbations in the tertiary structure and a concomitant rewiring of allosteric pathways, allowing us to describe how subtle changes may reshape energetic signaling. The results were analyzed in the context of other members of the PDZ family, which were found to contain distinct interaction pathways for different peptide ligands. The data reveal a fascinating scenario whereby several energetic pathways are sampled within one single domain and distinct pathways are activated by specific protein ligands.

U2 - 10.1016/j.str.2013.05.010

DO - 10.1016/j.str.2013.05.010

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JF - Structure

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Energetic pathway sampling in a protein interaction domain

Abstract

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