PDBsum entry 1lpb

Hydrolase(carboxylic esterase)

PDB id: 1lpb

Contents

Protein chains

85 a.a. *

449 a.a. *

Ligands

BOG ×5

MUP

Metals

_CA

Waters ×855

* Residue conservation analysis

PDB id:

1lpb

Name:

Hydrolase(carboxylic esterase)

Title:

The 2.46 angstroms resolution structure of the pancreatic lipase colipase complex inhibited by a c11 alkyl phosphonate

Structure:

Colipase. Chain: a. Engineered: yes. Lipase. Chain: b. Engineered: yes

Source:

Sus scrofa. Pig. Organism_taxid: 9823. Organ: pancreas. Homo sapiens. Human. Organism_taxid: 9606. Organ: pancreas

Biol. unit:

Dimer (from PQS)

Resolution:

2.46Å R-factor: 0.183 R-free: 0.285

Authors:

M.-P.Egloff,H.Van Tilbeurgh,C.Cambillau

Key ref:

M.P.Egloff et al. (1995). The 2.46 A resolution structure of the pancreatic lipase-colipase complex inhibited by a C11 alkyl phosphonate. Biochemistry, 34, 2751-2762. PubMed id: 7893686 DOI: 10.1021/bi00009a003

Date:

19-Aug-94 Release date: 01-Nov-94

Protein chain

P02703  (COL_PIG) -  Colipase from Sus scrofa

Seq: 112 a.a.

Struc: 85 a.a.*

Protein chain

P16233  (LIPP_HUMAN) -  Pancreatic triacylglycerol lipase from Homo sapiens

Seq: 465 a.a.

Struc: 449 a.a.

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

Enzyme reactions

• Enzyme class: Chain B: E.C.3.1.1.3 - triacylglycerol lipase.
• Reaction: a triacylglycerol + H2O = a diacylglycerol + a fatty acid + H⁺

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

reference

DOI no: 10.1021/bi00009a003

Biochemistry 34:2751-2762 (1995)

PubMed id: 7893686

The 2.46 A resolution structure of the pancreatic lipase-colipase complex inhibited by a C11 alkyl phosphonate.

M.P.Egloff, F.Marguet, G.Buono, R.Verger, C.Cambillau, H.van Tilbeurgh.

ABSTRACT

Pancreatic lipase belongs to the serine esterase family and can therefore be inhibited by classical serine reagents such as diisopropyl fluoride or E600. In an attempt to further characterize the active site and catalytic mechanism, we synthesized a C11 alkyl phosphonate compound. This compound is an effective inhibitor of pancreatic lipase. The crystal structure of the pancreatic lipase-colipase complex inhibited by this compound was determined at a resolution of 2.46 A and refined to a final R-factor of 18.3%. As was observed in the case of the structure of the ternary pancreatic lipase-colipase-phospholipid complex, the binding of the ligand induces rearrangements of two surface loops in comparison with the closed structure of the enzyme (van Tilbeurgh et al., 1993b). The inhibitor, which could be clearly observed in the active site, was covalently bound to the active site serine Ser152. A racemic mixture of the inhibitor was used in the crystallization, and there exists evidence that both enantiomers are bound at the active site. The C11 alkyl chain of the first enantiomer fits into a hydrophobic groove and is though to thus mimic the interaction between the leaving fatty acid of a triglyceride substrate and the protein. The alkyl chain of the second enantiomer also has an elongated conformation and interacts with hydrophobic patches on the surface of the open amphipathic lid. This may indicate the location of a second alkyl chain of a triglyceride substrate. Some of the detergent molecules, needed for the crystallization, were also observed in the crystal. Some of them were located at the entrance of the active site, bound to the hydrophobic part of the lid. On the basis of this crystallographic study, a hypothesis about the binding mode of real substrates and the organization of the active site is proposed.