Conformational transitions upon ligand binding: holo-structure prediction from apo conformations.

Biological function of proteins is frequently associated with the formation of complexes with small-molecule ligands. Experimental structure determination of such complexes at atomic resolution, however, can be time-consuming and costly. Computational methods for structure prediction of protein/liga...

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Autores principales:	Daniel Seeliger, Bert L de Groot
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2010
Materias:	Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/d87e69d23da54738b1c34e2d5de91957
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spelling	oai:doaj.org-article:d87e69d23da54738b1c34e2d5de919572021-11-25T05:42:43ZConformational transitions upon ligand binding: holo-structure prediction from apo conformations.1553-734X1553-735810.1371/journal.pcbi.1000634https://doaj.org/article/d87e69d23da54738b1c34e2d5de919572010-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/20066034/?tool=EBIhttps://doaj.org/toc/1553-734Xhttps://doaj.org/toc/1553-7358Biological function of proteins is frequently associated with the formation of complexes with small-molecule ligands. Experimental structure determination of such complexes at atomic resolution, however, can be time-consuming and costly. Computational methods for structure prediction of protein/ligand complexes, particularly docking, are as yet restricted by their limited consideration of receptor flexibility, rendering them not applicable for predicting protein/ligand complexes if large conformational changes of the receptor upon ligand binding are involved. Accurate receptor models in the ligand-bound state (holo structures), however, are a prerequisite for successful structure-based drug design. Hence, if only an unbound (apo) structure is available distinct from the ligand-bound conformation, structure-based drug design is severely limited. We present a method to predict the structure of protein/ligand complexes based solely on the apo structure, the ligand and the radius of gyration of the holo structure. The method is applied to ten cases in which proteins undergo structural rearrangements of up to 7.1 A backbone RMSD upon ligand binding. In all cases, receptor models within 1.6 A backbone RMSD to the target were predicted and close-to-native ligand binding poses were obtained for 8 of 10 cases in the top-ranked complex models. A protocol is presented that is expected to enable structure modeling of protein/ligand complexes and structure-based drug design for cases where crystal structures of ligand-bound conformations are not available.Daniel SeeligerBert L de GrootPublic Library of Science (PLoS)articleBiology (General)QH301-705.5ENPLoS Computational Biology, Vol 6, Iss 1, p e1000634 (2010)
institution	DOAJ
collection	DOAJ
language	EN
topic	Biology (General) QH301-705.5
spellingShingle	Biology (General) QH301-705.5 Daniel Seeliger Bert L de Groot Conformational transitions upon ligand binding: holo-structure prediction from apo conformations.
description	Biological function of proteins is frequently associated with the formation of complexes with small-molecule ligands. Experimental structure determination of such complexes at atomic resolution, however, can be time-consuming and costly. Computational methods for structure prediction of protein/ligand complexes, particularly docking, are as yet restricted by their limited consideration of receptor flexibility, rendering them not applicable for predicting protein/ligand complexes if large conformational changes of the receptor upon ligand binding are involved. Accurate receptor models in the ligand-bound state (holo structures), however, are a prerequisite for successful structure-based drug design. Hence, if only an unbound (apo) structure is available distinct from the ligand-bound conformation, structure-based drug design is severely limited. We present a method to predict the structure of protein/ligand complexes based solely on the apo structure, the ligand and the radius of gyration of the holo structure. The method is applied to ten cases in which proteins undergo structural rearrangements of up to 7.1 A backbone RMSD upon ligand binding. In all cases, receptor models within 1.6 A backbone RMSD to the target were predicted and close-to-native ligand binding poses were obtained for 8 of 10 cases in the top-ranked complex models. A protocol is presented that is expected to enable structure modeling of protein/ligand complexes and structure-based drug design for cases where crystal structures of ligand-bound conformations are not available.
format	article
author	Daniel Seeliger Bert L de Groot
author_facet	Daniel Seeliger Bert L de Groot
author_sort	Daniel Seeliger
title	Conformational transitions upon ligand binding: holo-structure prediction from apo conformations.
title_short	Conformational transitions upon ligand binding: holo-structure prediction from apo conformations.
title_full	Conformational transitions upon ligand binding: holo-structure prediction from apo conformations.
title_fullStr	Conformational transitions upon ligand binding: holo-structure prediction from apo conformations.
title_full_unstemmed	Conformational transitions upon ligand binding: holo-structure prediction from apo conformations.
title_sort	conformational transitions upon ligand binding: holo-structure prediction from apo conformations.
publisher	Public Library of Science (PLoS)
publishDate	2010
url	https://doaj.org/article/d87e69d23da54738b1c34e2d5de91957
work_keys_str_mv	AT danielseeliger conformationaltransitionsuponligandbindingholostructurepredictionfromapoconformations AT bertldegroot conformationaltransitionsuponligandbindingholostructurepredictionfromapoconformations
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Conformational transitions upon ligand binding: holo-structure prediction from apo conformations.

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