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PDBsum entry 6t5w
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References listed in PDB file
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Key reference
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Title
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Protein-Induced change in ligand protonation during trypsin and thrombin binding: hint on differences in selectivity determinants of both proteins?
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Authors
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K.Ngo,
C.Collins-Kautz,
S.Gerstenecker,
B.Wagner,
A.Heine,
G.Klebe.
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Ref.
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J Med Chem, 2020,
63,
3274-3289.
[DOI no: ]
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PubMed id
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Abstract
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Trypsin and thrombin, structurally similar serine proteases, recognize different
substrates; thrombin cleaves after Arg, whereas trypsin cleaves after Lys/Arg.
Both recognize basic substrate headgroups via Asp189 at the bottom of the S1
pocket. By crystallography and isothermal titration calorimetry (ITC), we
studied a series of d-Phe/d-DiPhe-Pro-(amino)pyridines. Identical ligand pairs
show the same binding poses. Surprisingly, one ligand binds to trypsin in
protonated state and to thrombin in unprotonated state at P1 along with
differences in the residual solvation pattern. While trypsin binding is mediated
by an ordered water molecule, in thrombin, water is scattered over three
hydration sites. Although having highly similar S1 pockets, our results suggest
different electrostatic properties of Asp189 possibly contributing to the
selectivity determinant. Thrombin binds a specific Na+ ion next to
Asp189, which is absent in trypsin. The electrostatic properties across the S1
pocket are further attenuated by charged Glu192 at the rim of S1 in thrombin,
which is replaced by uncharged Gln192 in trypsin.
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