PDBsum entry 1thl

Hydrolase/hydrolase inhibitor

PDB id: 1thl

Contents

Protein chain

316 a.a. *

Ligands

0DB

Metals

_CA ×4

_ZN

Waters ×148

* Residue conservation analysis

PDB id:

1thl

Name:

Hydrolase/hydrolase inhibitor

Title:

Thermolysin complexed with a novel glutaramide derivative, n-(1-(2(r, s)-carboxy-4-phenylbutyl) cyclopentylcarbonyl)-(s)-tryptophan

Structure:

Thermolysin. Chain: a. Ec: 3.4.24.27

Source:

Bacillus thermoproteolyticus. Organism_taxid: 1427

Biol. unit:

Dimer (from PQS)

Resolution:

1.70Å R-factor: 0.162

Authors:

D.R.Holland,B.W.Matthews

Key ref:

D.R.Holland et al. (1994). Inhibition of thermolysin and neutral endopeptidase 24.11 by a novel glutaramide derivative: X-ray structure determination of the thermolysin-inhibitor complex. Biochemistry, 33, 51-56. PubMed id: 8286362 DOI: 10.1021/bi00167a007

Date:

17-Nov-93 Release date: 31-Jan-94

Protein chain

P00800  (THER_BACTH) -  Thermolysin from Bacillus thermoproteolyticus

Seq: 548 a.a.

Struc: 316 a.a.*

* PDB and UniProt seqs differ at 2 residue positions (black crosses)

Enzyme reactions

• Enzyme class: E.C.3.4.24.27 - thermolysin.
• Reaction: Preferential cleavage: Xaa-|-Leu > Xaa-|-Phe.
• Cofactor: Ca(2+); Zn(2+)

DOI no: 10.1021/bi00167a007

Biochemistry 33:51-56 (1994)

PubMed id: 8286362

Inhibition of thermolysin and neutral endopeptidase 24.11 by a novel glutaramide derivative: X-ray structure determination of the thermolysin-inhibitor complex.

D.R.Holland, P.L.Barclay, J.C.Danilewicz, B.W.Matthews, K.James.

ABSTRACT

Determination of the X-ray structure of thermolysin-inhibitor complexes has proven useful in aiding our understanding of the mode of binding of inhibitors of related, physiologically important, mammalian zinc peptidases including neutral endopeptidase EC 3.4.24.11 and angiotensin-converting enzyme. Here we describe the mode of binding to crystalline thermolysin of N-[1-(2(R,S)-carboxy-4-phenylbutyl)-cyclopentylcarbonyl]-(S) -tryptophan (CCT). CCT is an analogue of both candoxatrilat, a potent inhibitor of neutral endopeptidase 24.11, and of the 5-indanyl ester prodrug candoxatril, which is under clinical evaluation as a potential therapy for congestive heart failure. CCT differs from the previously studied N-carboxyalkyl dipeptide CLT [N-(S)-(1-carboxy-3-phenylpropyl)-(S)-leucyl-(S)-tryptophan] in several important respects. It has a highly constrained gem-cyclopentyl P1' substituent and lacks the characteristic imino nitrogen substituent of CLT. The structure determination shows that, notwithstanding the conformational influence of the gem-cyclopentyl substituent, CCT binds within the active site of thermolysin in a similar manner to CLT. Although the characteristic hydrogen bond between the imino nitrogen of CLT and thermolysin is absent in CCT, the affinities of the two inhibitors for the enzyme are virtually identical. These results illustrate the importance of considering not only those hydrogen bonds that are formed in an enzyme-ligand complex but also the other hydrogen bonds that may be lost due to desolvation of the enzyme and ligand on formation of the complex. In addition, the overall conformational demands placed upon a ligand in order to achieve receptor interaction may be critically important.