Structure of human neutrophil elastase in complex with a peptide chloromethyl ketone inhibitor at 1.84-A resolution.
Human neutrophil elastase (HNE) has been implicated as a major contributor to tissue destruction in various disease states, including emphysema. The structure of HNE, at neutral pH, in complex with methoxysuccinyl-Ala-Ala-Pro-Ala chloromethyl ketone (MSACK), has been solved and refined to an R factor of 16.4% at 1.84-A resolution. Results are consistent with the currently accepted mechanism of peptide chloromethyl ketone inhibition of serine proteases, in that MSACK cross-links the catalytic residues His-57 and Ser-195. The structure of the HNE-MSACK complex is compared with that of porcine pancreatic elastase in complex with L-647,957, a beta-lactam inhibitor of both elastases. The distribution of positively charged residues on HNE is highly asymmetric and may play a role in its specific association with the underlying negatively charged proteoglycan matrix of the neutrophil granules in which the enzyme is stored.
Navia
M A
MA
Merck Sharp & Dohme Research Laboratories, Rahway, NJ 07065.
McKeever
B M
BM
Springer
J P
JP
Lin
T Y
TY
Williams
H R
HR
Fluder
E M
EM
Dorn
C P
CP
Hoogsteen
K
K
D000590:Amino Acid Chloromethyl Ketones / Q000378:metabolism*; D001665:Binding Sites; D006801:Humans; D008958:Models, Molecular; D009504:Neutrophils / Q000201:enzymology*; D010196:Pancreatic Elastase / Q000037:antagonists & inhibitors / Q000097:blood*; D011485:Protein Binding; D011487:Protein Conformation; D013183:Sputum / Q000201:enzymology; D014961:X-Ray Diffraction
D000590:Amino Acid Chloromethyl Ketones; C058167:methoxysuccinyl-alanyl-alanyl-prolyl-alanine chloromethyl ketone; D010196:Pancreatic Elastase