PDBsum entry 1thl

Hydrolase/hydrolase inhibitor

PDB id: 1thl

Contents

Protein chain

316 a.a.

Ligands

0DB

Metals

_CA ×4

_ZN

Waters ×148

References listed in PDB file

Key reference

Title

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

Authors

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

Ref.

Biochemistry, 1994, 33, 51-56. [DOI no: 10.1021/bi00167a007]

PubMed id

8286362

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.

Secondary reference #1

Title

Binding of n-Carboxymethyl dipeptide inhibitors to thermolysin determined by x-Ray crystallography: a novel class of transition-State analogues for zinc peptidases.

Authors

A.F.Monzingo, B.W.Matthews.

Ref.

Biochemistry, 1984, 23, 5724-5729. [DOI no: 10.1021/bi00319a010]

PubMed id

6395881

Secondary reference #2

Title

Structure of thermolysin refined at 1.6 a resolution.

Authors

M.A.Holmes, B.W.Matthews.

Ref.

J Mol Biol, 1982, 160, 623-639. [DOI no: 10.1016/0022-2836(82)90319-9]

PubMed id

7175940

Figure 3.
FIG. 3. Conformational diagram for the backbone of thermolysin. Residues that are outside the ``allowed'' regions for a hard-sphere model are numbered.

Figure 4.
FIG. 4. Stereo diagram illustrating the apparent thermal motion of t,he thermolysin molecule. Larger circles correspond to residues with greater apparen motion. The radius of each c~wlr l\as obtained 1)~ taking the verage R value for all atoms in that residue, subtracting a constant value of 4.0 AZ (in order to make differences in apparent motion more obvious) and drawing the circle at t,hr SO'?; probabilit? level (Johson, 196.5).

The above figures are reproduced from the cited reference with permission from Elsevier

Secondary reference #3

Title

The conformation of thermolysin.

Authors

B.W.Matthews, L.H.Weaver, W.R.Kester.

Ref.

J Biol Chem, 1974, 249, 8030-8044.

PubMed id

4214815

Secondary reference #4

Title

Structure of thermolysin

Authors

B.W.Matthews, P.M.Colman, J.N.Jansonius, K.Titani, K.A.Walsh, H.Neura.

Ref.

nature new biol, 1972, 238, 41.

Secondary reference #5

Title

Three dimensional structure of thermolysin

Authors

B.W.Matthews, J.N.Jansonius, P.N.Colman, B.P.Schoenborn, D.Duporque.

Ref.

nature new biol, 1972, 238, 37.