PDBsum entry 1bjv

Serine protease

PDB id: 1bjv

Contents

Protein chain

223 a.a. *

Ligands

SO4 ×2

DMS

GP8

Metals

_CA

Waters ×165

* Residue conservation analysis

PDB id:

1bjv

Name:

Serine protease

Title:

Beta-trypsin complexed with appu

Structure:

Beta-trypsin. Chain: a. Ec: 3.4.21.4

Source:

Bos taurus. Cattle. Organism_taxid: 9913. Organ: pancreas

Resolution:

1.80Å R-factor: 0.196

Authors:

S.Presnell,G.Patil,C.Mura,K.Jude,J.Conley,C.Kam,J.Bertrand,J.Powers, L.Williams

Key ref:

S.R.Presnell et al. (1998). Oxyanion-mediated inhibition of serine proteases. Biochemistry, 37, 17068-17081. PubMed id: 9836602

Date:

29-Jun-98 Release date: 02-Dec-98

Protein chain

P00760  (TRY1_BOVIN) -  Serine protease 1 from Bos taurus

Seq: 246 a.a.

Struc: 223 a.a.

Enzyme reactions

• Enzyme class: E.C.3.4.21.4 - trypsin.
• Reaction: Preferential cleavage: Arg-|-Xaa, Lys-|-Xaa.

Biochemistry 37:17068-17081 (1998)

PubMed id: 9836602

Oxyanion-mediated inhibition of serine proteases.

S.R.Presnell, G.S.Patil, C.Mura, K.M.Jude, J.M.Conley, J.A.Bertrand, C.M.Kam, J.C.Powers, L.D.Williams.

ABSTRACT

Novel aryl derivatives of benzamidine were synthesized and tested for their inhibitory potency against bovine trypsin, rat skin tryptase, human recombinant granzyme A, human thrombin, and human plasma kallikrein. All compounds show competitive inhibition against these proteases with Ki values in the micromolar range. X-ray structures were determined to 1.8 A resolution for trypsin complexed with two of the para-substituted benzamidine derivatives, 1-(4-amidinophenyl)-3-(4-chlorophenyl)urea (ACPU) and 1-(4-amidinophenyl)-3-(4-phenoxyphenyl)urea (APPU). Although the inhibitors do not engage in direct and specific interactions outside the S1 pocket, they do form intimate indirect contacts with the active site of trypsin. The inhibitors are linked to the enzyme by a sulfate ion that forms an intricate network of three-centered hydrogen bonds. Comparison of these structures with other serine protease structures with noncovalently bound oxyanions reveals a pair of highly conserved oxyanion-binding sites in the active site. The positions of noncovalently bound oxyanions, such as the oxygen atoms of sulfate, are distinct from the positions of covalent oxyanions of tetrahedral intermediates. Noncovalent oxyanion positions are outside the "oxyanion hole." Kinetics data suggest that protonation stabilizes the ternary inhibitor/oxyanion/protease complex. In sum, both cations and anions can mediate Ki. Cation mediation of potency of competitive inhibitors of serine proteases was previously reported by Stroud and co-workers [Katz, B. A., Clark, J. M., Finer-Moore, J. S., Jenkins, T. E., Johnson, C. R., Ross, M. J., Luong, C., Moore, W. R., and Stroud, R. M. (1998) Nature 391, 608-612].