Use of cyclic peptides to induce crystallization: case study with prolyl hydroxylase domain 2

Abstract Crystallization is the bottleneck in macromolecular crystallography; even when a protein crystallises, crystal packing often influences ligand-binding and protein–protein interaction interfaces, which are the key points of interest for functional and drug discovery studies. The human hypoxi...

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Autores principales:	Rasheduzzaman Chowdhury, Martine I. Abboud, Tom E. McAllister, Biswadip Banerji, Bhaskar Bhushan, John L. Sorensen, Akane Kawamura, Christopher J. Schofield
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2020
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/7ffb0667b88f4bb4a12b5e6a229217a5
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spelling	oai:doaj.org-article:7ffb0667b88f4bb4a12b5e6a229217a52021-12-02T13:58:13ZUse of cyclic peptides to induce crystallization: case study with prolyl hydroxylase domain 210.1038/s41598-020-76307-82045-2322https://doaj.org/article/7ffb0667b88f4bb4a12b5e6a229217a52020-12-01T00:00:00Zhttps://doi.org/10.1038/s41598-020-76307-8https://doaj.org/toc/2045-2322Abstract Crystallization is the bottleneck in macromolecular crystallography; even when a protein crystallises, crystal packing often influences ligand-binding and protein–protein interaction interfaces, which are the key points of interest for functional and drug discovery studies. The human hypoxia-inducible factor prolyl hydroxylase 2 (PHD2) readily crystallises as a homotrimer, but with a sterically blocked active site. We explored strategies aimed at altering PHD2 crystal packing by protein modification and molecules that bind at its active site and elsewhere. Following the observation that, despite weak inhibition/binding in solution, succinamic acid derivatives readily enable PHD2 crystallization, we explored methods to induce crystallization without active site binding. Cyclic peptides obtained via mRNA display bind PHD2 tightly away from the active site. They efficiently enable PHD2 crystallization in different forms, both with/without substrates, apparently by promoting oligomerization involving binding to the C-terminal region. Although our work involves a specific case study, together with those of others, the results suggest that mRNA display-derived cyclic peptides may be useful in challenging protein crystallization cases.Rasheduzzaman ChowdhuryMartine I. AbboudTom E. McAllisterBiswadip BanerjiBhaskar BhushanJohn L. SorensenAkane KawamuraChristopher J. SchofieldNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 10, Iss 1, Pp 1-11 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Rasheduzzaman Chowdhury Martine I. Abboud Tom E. McAllister Biswadip Banerji Bhaskar Bhushan John L. Sorensen Akane Kawamura Christopher J. Schofield Use of cyclic peptides to induce crystallization: case study with prolyl hydroxylase domain 2
description	Abstract Crystallization is the bottleneck in macromolecular crystallography; even when a protein crystallises, crystal packing often influences ligand-binding and protein–protein interaction interfaces, which are the key points of interest for functional and drug discovery studies. The human hypoxia-inducible factor prolyl hydroxylase 2 (PHD2) readily crystallises as a homotrimer, but with a sterically blocked active site. We explored strategies aimed at altering PHD2 crystal packing by protein modification and molecules that bind at its active site and elsewhere. Following the observation that, despite weak inhibition/binding in solution, succinamic acid derivatives readily enable PHD2 crystallization, we explored methods to induce crystallization without active site binding. Cyclic peptides obtained via mRNA display bind PHD2 tightly away from the active site. They efficiently enable PHD2 crystallization in different forms, both with/without substrates, apparently by promoting oligomerization involving binding to the C-terminal region. Although our work involves a specific case study, together with those of others, the results suggest that mRNA display-derived cyclic peptides may be useful in challenging protein crystallization cases.
format	article
author	Rasheduzzaman Chowdhury Martine I. Abboud Tom E. McAllister Biswadip Banerji Bhaskar Bhushan John L. Sorensen Akane Kawamura Christopher J. Schofield
author_facet	Rasheduzzaman Chowdhury Martine I. Abboud Tom E. McAllister Biswadip Banerji Bhaskar Bhushan John L. Sorensen Akane Kawamura Christopher J. Schofield
author_sort	Rasheduzzaman Chowdhury
title	Use of cyclic peptides to induce crystallization: case study with prolyl hydroxylase domain 2
title_short	Use of cyclic peptides to induce crystallization: case study with prolyl hydroxylase domain 2
title_full	Use of cyclic peptides to induce crystallization: case study with prolyl hydroxylase domain 2
title_fullStr	Use of cyclic peptides to induce crystallization: case study with prolyl hydroxylase domain 2
title_full_unstemmed	Use of cyclic peptides to induce crystallization: case study with prolyl hydroxylase domain 2
title_sort	use of cyclic peptides to induce crystallization: case study with prolyl hydroxylase domain 2
publisher	Nature Portfolio
publishDate	2020
url	https://doaj.org/article/7ffb0667b88f4bb4a12b5e6a229217a5
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Use of cyclic peptides to induce crystallization: case study with prolyl hydroxylase domain 2

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