 |
PDBsum entry 1qr3
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Hydrolase/hydrolase inhibitor
|
PDB id
|
|
|
|
1qr3
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
Contents |
 |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
* Residue conservation analysis
|
|
|
|
|
References listed in PDB file
|
|
|
Key reference
|
|
|
Title
|
|
Structure of porcine pancreatic elastase complexed with fr901277, A novel macrocyclic inhibitor of elastases, At 1.6 a resolution.
|
|
|
Authors
|
|
I.Nakanishi,
T.Kinoshita,
A.Sato,
T.Tada.
|
|
|
Ref.
|
|
Biopolymers, 2000,
53,
434-445.
|
|
|
PubMed id
|
|
|
|
|
|
Abstract
|
|
|
Human leukocyte elastase (HLE) is a serine protease that contributes to tissue
destruction in various disease states-for example, in emphysema. FR901277 is a
natural product isolated from the culture filtrate of Streptomyces
resistomicificus and is a potent inhibitor of both HLE and porcine pancreatic
elastase (PPE). FR901277 consists of four normal amino acids and three unusual
amino acids, and is a unique bicyclic peptide compound. The crystal structure of
PPE complexed with FR901277 has been determined at 1.6 A resolution. The Ogamma
atom of Ser-195 in PPE did not form a covalent bond with FR901277, but formed a
hydrogen bond with the Nvarepsilon atom of His-57. On the other hand, the
portion from L-Orn(1) through dehydroxyThr(3) in FR901277 formed an antiparallel
beta-sheet structure with the backbone of the active site in PPE. The S4 through
S2' binding subsites in PPE were all occupied by the hydrophobic side chains of
the inhibitor molecule. Especially, the ethylidene moiety of FR901277 occupied
the S1 specific pocket, indicating a CH/pi interaction. In addition, the
isopropyl side chain of L-Val(7) was located at the enzyme surface between the
S2 and S1' pockets with several van der Waals contacts. However, the amino acid
(4) residue was not involved in a significant interaction with PPE. Comparison
of inhibitor structures in different environments showed that FR901277 has a
highly rigid bicyclic framework; however, it can slightly change its
conformation according to the circumstances. The binding mode of FR901277 at the
active site of PPE was directly applicable to that in HLE, after consideration
of induced fit. The structure of the PPE-FR901277 complex provided much
information regarding potential sites for modification of the physicochemical
properties of FR901277.
|
|
|
|
|
|
|
