Structure of human ADAM-8 catalytic domain complexed with batimastat.
The role of ADAM-8 in cancer and inflammatory diseases such as allergy, arthritis and asthma makes it an attractive target for drug development. Therefore, the catalytic domain of human ADAM-8 was expressed, purified and crystallized in complex with a hydroxamic acid inhibitor, batimastat. The crystal structure of the enzyme-inhibitor complex was refined to 2.1 Å resolution. ADAM-8 has an overall fold similar to those of other ADAM members, including a central five-stranded β-sheet and a catalytic Zn(2+) ion. However, unique differences within the S1' binding loop of ADAM-8 are observed which might be exploited to confer specificity and selectivity to ADAM-8 competitive inhibitors for the treatment of diseases involving this enzyme.
Pfizer Inc, 700 Chesterfield Parkway West, Chesterfield, MO 63017, USA.
Troii
T
Hall
Huey Sheng
HS
Shieh
Jacqueline E
JE
Day
Nicole
N
Caspers
Jill E
JE
Chrencik
Jennifer M
JM
Williams
Lyle E
LE
Pegg
Adele M
AM
Pauley
Andrea F
AF
Moon
Joseph M
JM
Krahn
David H
DH
Fischer
James R
JR
Kiefer
Alfredo G
AG
Tomasselli
Marc D
MD
Zack
D051722:ADAM Proteins / Q000737:chemistry* / Q000378:metabolism; D020134:Catalytic Domain; D006801:Humans; D008024:Ligands; D008565:Membrane Proteins / Q000737:chemistry* / Q000378:metabolism; D008958:Models, Molecular; D010649:Phenylalanine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism; D011480:Protease Inhibitors / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding; D058767:Protein Unfolding; D013876:Thiophenes / Q000737:chemistry* / Q000378:metabolism
D008024:Ligands; D008565:Membrane Proteins; D011480:Protease Inhibitors; D013876:Thiophenes; D010649:Phenylalanine; C080985:batimastat; D051722:ADAM Proteins; C068490:ADAM8 protein, human