PDBsum entry 1qr3

Hydrolase/hydrolase inhibitor

PDB id: 1qr3

Contents

Protein chain

240 a.a. *

Ligands

ALQ-CIR-THR-DBU-GLJ-PHE-TYJ-VAL

SO4

Metals

_CA

Waters ×337

* Residue conservation analysis

PDB id:

1qr3

Name:

Hydrolase/hydrolase inhibitor

Title:

Structure of porcine pancreatic elastase in complex with fr901277, a novel macrocyclic inhibitor of elastases at 1.6 angstrom resolution

Structure:

Chymotrypsin-like elastase family member 1. Chain: e. Synonym: elastase-1. Fr901277 inhibitor. Chain: i

Source:

Sus scrofa. Pig. Organism_taxid: 9823. Other_details: porcine pancreas. Streptomyces resistomycificus. Organism_taxid: 67356

Biol. unit:

Dimer (from PQS)

Resolution:

1.60Å R-factor: 0.197

Authors:

I.Nakanishi,T.Kinoshita,A.Sato,T.Tada

Key ref:

I.Nakanishi et al. (2000). Structure of porcine pancreatic elastase complexed with FR901277, a novel macrocyclic inhibitor of elastases, at 1.6 A resolution. Biopolymers, 53, 434-445. PubMed id: 10738204

Date:

18-Jun-99 Release date: 21-Jun-00

Protein chain

P00772  (CELA1_PIG) -  Chymotrypsin-like elastase family member 1 from Sus scrofa

Seq: 266 a.a.

Struc: 240 a.a.*

* PDB and UniProt seqs differ at 1 residue position (black cross)

Enzyme reactions

• Enzyme class: E.C.3.4.21.36 - pancreatic elastase.
• Reaction: Hydrolysis of proteins, including elastin. Preferential cleavage: Ala-|-Xaa.

Biopolymers 53:434-445 (2000)

PubMed id: 10738204

Structure of porcine pancreatic elastase complexed with FR901277, a novel macrocyclic inhibitor of elastases, at 1.6 A resolution.

I.Nakanishi, T.Kinoshita, A.Sato, T.Tada.

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.