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1thl

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{{STRUCTURE_1thl| PDB=1thl | SCENE= }}
{{STRUCTURE_1thl| PDB=1thl | SCENE= }}
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'''Thermolysin complexed with a novel glutaramide derivative, n-(1-(2(r,s)-carboxy-4-phenylbutyl) cyclopentylcarbonyl)-(s)-tryptophan'''
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===Thermolysin complexed with a novel glutaramide derivative, n-(1-(2(r,s)-carboxy-4-phenylbutyl) cyclopentylcarbonyl)-(s)-tryptophan===
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==Overview==
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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.
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==About this Structure==
==About this Structure==
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[[Category: Holland, D R.]]
[[Category: Holland, D R.]]
[[Category: Matthews, B W.]]
[[Category: Matthews, B W.]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Tue Jul 29 05:52:54 2008''

Revision as of 02:52, 29 July 2008

Image:1thl.png

Template:STRUCTURE 1thl

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

Template:ABSTRACT PUBMED 8286362

About this Structure

1THL is a Single protein structure of sequence from Bacillus thermoproteolyticus. Full crystallographic information is available from OCA.

Reference

Inhibition of thermolysin and neutral endopeptidase 24.11 by a novel glutaramide derivative: X-ray structure determination of the thermolysin-inhibitor complex., Holland DR, Barclay PL, Danilewicz JC, Matthews BW, James K, Biochemistry. 1994 Jan 11;33(1):51-6. PMID:8286362

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