Journal Article

IMPULSE-2021-00284

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png How a Fragment Draws Attention to Selectivity Discriminating Features between the Related Proteases Trypsin and Thrombin

Sandner, A. ; Ngo, K. ; Schiebel, J. ; Pizarroso, A. I. M. ; Schmidt, L. ; Wenzel, B. ; Steinmetzer, T. ; Ostermann, A.MLZ* ; Heine, A. ; Klebe, G. (Corresponding author)

2021
ACS Washington, DC

Please use a persistent id in citations: doi:10.1021/acs.jmedchem.0c01809

Abstract: In the S1 pocket, the serine proteases thrombin and trypsin commonly feature Asp189 and a Ala190Ser and Glu192Gln exchange. Nevertheless, thrombin cleaves peptide chains solely after Arg, and trypsin after Lys and Arg. Thrombin exhibits a Na+-binding site next to Asp189, which is missing in trypsin. The fragment benzylamine shows direct H bonding to Asp189 in trypsin, while in thrombin, it forms an H-bond to Glu192. A series of fragments and expanded ligands were studied against both enzymes and mutated variants by crystallography and ITC. The selectivity-determining features of both S1 pockets are difficult to assign to one dominating factor. The Ala190Ser and Glu192Gln replacements may be regarded as highly conserved as no structural and affinity changes are observed between both proteases. With respect to charge distribution, Glu192, together with the thrombin- specific sodium ion, helps in creating an electrostatic gradient across the S1 pocket. This feature is definitely absent in trypsin but important for selectivity along with solvation-pattern differences in the S1 pocket.

Keyword(s): Health and Life (1st) ; Biology (2nd) ; Crystallography (2nd)

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Contributing Institute(s):

1. BIODIFF (BIODIFF)
2. STRUCTURE (STRUCTURE)

Experiment(s):

1. BIODIFF: Diffractometer for large unit cells (NL1)

Appears in the scientific report 2021

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Database coverage:
; BIOSIS Previews ; Biological Abstracts ; Chemical Reactions ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; Ebsco Academic Search ; Essential Science Indicators ; IF >= 5 ; Index Chemicus ; JCR ; Nationallizenz ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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