Universität zu Köln

Hochscherf, Jennifer ORCID: 0000-0002-4412-7391, Pietsch, Markus, Tieu, William ORCID: 0000-0002-7161-4152, Kuan, Kevin, Abell, Andrew D., Guetschow, Michael and Niefind, Karsten ORCID: 0000-0002-0183-6315 (2018). Crystal structure of highly glycosylated human leukocyte elastase in complex with an S2 ' site binding inhibitor. Acta Crystallogr. F-Struct. Biol. Commun., 74. S. 480 - 490. CHESTER: INT UNION CRYSTALLOGRAPHY. ISSN 2053-230X

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Abstract

Glycosylated human leukocyte elastase (HLE) was crystallized and structurally analysed in complex with a 1,3-thiazolidine-2,4-dione derivative that had been identified as an HLE inhibitor in preliminary studies. In contrast to previously described HLE structures with small-molecule inhibitors, in this structure the inhibitor does not bind to the Si and S2 substrate-recognition sites; rather, this is the first HLE structure with a synthetic inhibitor in which the S2' site is blocked that normally binds the second side chain at the C-terminal side of the scissile peptide bond in a substrate protein. The inhibitor also induces the formation of crystalline HLE dimers that block access to the active sites and that are also predicted to be stable in solution. Neither such HLE dimers nor the corresponding crystal packing have been observed in previous HLE crystal structures. This novel crystalline environment contributes to the observation that comparatively large parts of the N-glycan chains of HLE are defined by electron density. The final HLE structure contains the largest structurally defined carbohydrate trees among currently available HLE structures.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Hochscherf, Jennifer UNSPECIFIED orcid.org/0000-0002-4412-7391 UNSPECIFIED Pietsch, Markus UNSPECIFIED UNSPECIFIED UNSPECIFIED Tieu, William UNSPECIFIED orcid.org/0000-0002-7161-4152 UNSPECIFIED Kuan, Kevin UNSPECIFIED UNSPECIFIED UNSPECIFIED Abell, Andrew D. UNSPECIFIED UNSPECIFIED UNSPECIFIED Guetschow, Michael UNSPECIFIED UNSPECIFIED UNSPECIFIED Niefind, Karsten UNSPECIFIED orcid.org/0000-0002-0183-6315 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-178470
DOI:	10.1107/S2053230X1800537X
Journal or Publication Title:	Acta Crystallogr. F-Struct. Biol. Commun.
Volume:	74
Page Range:	S. 480 - 490
Date:	2018
Publisher:	INT UNION CRYSTALLOGRAPHY
Place of Publication:	CHESTER
ISSN:	2053-230X
Language:	English
Faculty:	Faculty of Mathematics and Natural Sciences
Divisions:	Faculty of Mathematics and Natural Sciences > Department of Chemistry > Institute of Biochemistry
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language HUMAN NEUTROPHIL ELASTASE; ACTIVE-SITE; PROTEIN; MECHANISM; IDENTIFICATION; FLEXIBILITY; THROMBIN; GRANULES; POTENT; MODEL Multiple languages Biochemical Research Methods; Biochemistry & Molecular Biology; Biophysics; Crystallography Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/17847