The role of flexibility and conformational selection in the binding promiscuity of PDZ domains.

In molecular recognition, it is often the case that ligand binding is coupled to conformational change in one or both of the binding partners. Two hypotheses describe the limiting cases involved; the first is the induced fit and the second is the conformational selection model. The conformational se...

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Autores principales:	Márton Münz, Jotun Hein, Philip C Biggin
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2012
Materias:	Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/e1a23253ad774166b7c92fe7029da4ad
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spelling	oai:doaj.org-article:e1a23253ad774166b7c92fe7029da4ad2021-11-18T05:52:44ZThe role of flexibility and conformational selection in the binding promiscuity of PDZ domains.1553-734X1553-735810.1371/journal.pcbi.1002749https://doaj.org/article/e1a23253ad774166b7c92fe7029da4ad2012-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23133356/pdf/?tool=EBIhttps://doaj.org/toc/1553-734Xhttps://doaj.org/toc/1553-7358In molecular recognition, it is often the case that ligand binding is coupled to conformational change in one or both of the binding partners. Two hypotheses describe the limiting cases involved; the first is the induced fit and the second is the conformational selection model. The conformational selection model requires that the protein adopts conformations that are similar to the ligand-bound conformation in the absence of ligand, whilst the induced-fit model predicts that the ligand-bound conformation of the protein is only accessible when the ligand is actually bound. The flexibility of the apo protein clearly plays a major role in these interpretations. For many proteins involved in signaling pathways there is the added complication that they are often promiscuous in that they are capable of binding to different ligand partners. The relationship between protein flexibility and promiscuity is an area of active research and is perhaps best exemplified by the PDZ domain family of proteins. In this study we use molecular dynamics simulations to examine the relationship between flexibility and promiscuity in five PDZ domains: the human Dvl2 (Dishevelled-2) PDZ domain, the human Erbin PDZ domain, the PDZ1 domain of InaD (inactivation no after-potential D protein) from fruit fly, the PDZ7 domain of GRIP1 (glutamate receptor interacting protein 1) from rat and the PDZ2 domain of PTP-BL (protein tyrosine phosphatase) from mouse. We show that despite their high structural similarity, the PDZ binding sites have significantly different dynamics. Importantly, the degree of binding pocket flexibility was found to be closely related to the various characteristics of peptide binding specificity and promiscuity of the five PDZ domains. Our findings suggest that the intrinsic motions of the apo structures play a key role in distinguishing functional properties of different PDZ domains and allow us to make predictions that can be experimentally tested.Márton MünzJotun HeinPhilip C BigginPublic Library of Science (PLoS)articleBiology (General)QH301-705.5ENPLoS Computational Biology, Vol 8, Iss 11, p e1002749 (2012)
institution	DOAJ
collection	DOAJ
language	EN
topic	Biology (General) QH301-705.5
spellingShingle	Biology (General) QH301-705.5 Márton Münz Jotun Hein Philip C Biggin The role of flexibility and conformational selection in the binding promiscuity of PDZ domains.
description	In molecular recognition, it is often the case that ligand binding is coupled to conformational change in one or both of the binding partners. Two hypotheses describe the limiting cases involved; the first is the induced fit and the second is the conformational selection model. The conformational selection model requires that the protein adopts conformations that are similar to the ligand-bound conformation in the absence of ligand, whilst the induced-fit model predicts that the ligand-bound conformation of the protein is only accessible when the ligand is actually bound. The flexibility of the apo protein clearly plays a major role in these interpretations. For many proteins involved in signaling pathways there is the added complication that they are often promiscuous in that they are capable of binding to different ligand partners. The relationship between protein flexibility and promiscuity is an area of active research and is perhaps best exemplified by the PDZ domain family of proteins. In this study we use molecular dynamics simulations to examine the relationship between flexibility and promiscuity in five PDZ domains: the human Dvl2 (Dishevelled-2) PDZ domain, the human Erbin PDZ domain, the PDZ1 domain of InaD (inactivation no after-potential D protein) from fruit fly, the PDZ7 domain of GRIP1 (glutamate receptor interacting protein 1) from rat and the PDZ2 domain of PTP-BL (protein tyrosine phosphatase) from mouse. We show that despite their high structural similarity, the PDZ binding sites have significantly different dynamics. Importantly, the degree of binding pocket flexibility was found to be closely related to the various characteristics of peptide binding specificity and promiscuity of the five PDZ domains. Our findings suggest that the intrinsic motions of the apo structures play a key role in distinguishing functional properties of different PDZ domains and allow us to make predictions that can be experimentally tested.
format	article
author	Márton Münz Jotun Hein Philip C Biggin
author_facet	Márton Münz Jotun Hein Philip C Biggin
author_sort	Márton Münz
title	The role of flexibility and conformational selection in the binding promiscuity of PDZ domains.
title_short	The role of flexibility and conformational selection in the binding promiscuity of PDZ domains.
title_full	The role of flexibility and conformational selection in the binding promiscuity of PDZ domains.
title_fullStr	The role of flexibility and conformational selection in the binding promiscuity of PDZ domains.
title_full_unstemmed	The role of flexibility and conformational selection in the binding promiscuity of PDZ domains.
title_sort	role of flexibility and conformational selection in the binding promiscuity of pdz domains.
publisher	Public Library of Science (PLoS)
publishDate	2012
url	https://doaj.org/article/e1a23253ad774166b7c92fe7029da4ad
work_keys_str_mv	AT martonmunz theroleofflexibilityandconformationalselectioninthebindingpromiscuityofpdzdomains AT jotunhein theroleofflexibilityandconformationalselectioninthebindingpromiscuityofpdzdomains AT philipcbiggin theroleofflexibilityandconformationalselectioninthebindingpromiscuityofpdzdomains AT martonmunz roleofflexibilityandconformationalselectioninthebindingpromiscuityofpdzdomains AT jotunhein roleofflexibilityandconformationalselectioninthebindingpromiscuityofpdzdomains AT philipcbiggin roleofflexibilityandconformationalselectioninthebindingpromiscuityofpdzdomains
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The role of flexibility and conformational selection in the binding promiscuity of PDZ domains.

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