STRUCTURAL-ANALYSIS OF THE ACTIVE-SITE OF PORCINE PANCREATIC ELASTASEBASED ON THE X-RAY CRYSTAL-STRUCTURES OF COMPLEXES WITH TRIFLUOROACETYL-DIPEPTIDE-ANILIDE INHIBITORS
C. Mattos et al., STRUCTURAL-ANALYSIS OF THE ACTIVE-SITE OF PORCINE PANCREATIC ELASTASEBASED ON THE X-RAY CRYSTAL-STRUCTURES OF COMPLEXES WITH TRIFLUOROACETYL-DIPEPTIDE-ANILIDE INHIBITORS, Biochemistry, 34(10), 1995, pp. 3193-3203
The X-ray crystal structures of two new (trifluoroacetyl)dipeptide p-(
trifluoromethyl)anilide (TFA-dipeptide-TFM) inhibitors complexed to po
rcine pancreatic elastase are presented. TFA-Val-Ala-TFM and TFA-Phe-A
la-TFM both bind to elastase with the TFA group in the S1 subsite, Val
or Phe in the S2 subsite, Ala in the S3 subsite, and the TFM group in
the S4 subsite. Five other TFA-dipeptide-anilide/elastase crystal str
uctures are available (two TFA-X-Ala-p-(trifluoromethyl)anilide, X = L
ys, Leu, and three TFA-Lys-X-p-isopropylanilide, X = Pro, Leu, Phe). T
he four inhibitors with the trifluoromethyl substituent on the anilide
ring bind in a single mode to elastase, whereas superposition of the
three inhibitors with the isopropyl substituent on the anilide ring sh
ow three different modes of binding to the protein [Mattos, C., et al.
(1994) Nature Struct. Biol. 1, 55-58]. The seven structures are taken
together in a detailed analysis of the active site of porcine pancrea
tic elastase. The inhibition constants for the inhibitors are used in
combination with the crystal structures to understand the specificity
of the different elastase subsites.