1tmn
From Proteopedia
(New page: 200px<br /><applet load="1tmn" size="450" color="white" frame="true" align="right" spinBox="true" caption="1tmn, resolution 1.9Å" /> '''BINDING OF N-CARBOXYM...) |
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| - | [[Image:1tmn.jpg|left|200px]]<br /><applet load="1tmn" size=" | + | [[Image:1tmn.jpg|left|200px]]<br /><applet load="1tmn" size="350" color="white" frame="true" align="right" spinBox="true" |
caption="1tmn, resolution 1.9Å" /> | caption="1tmn, resolution 1.9Å" /> | ||
'''BINDING OF N-CARBOXYMETHYL DIPEPETIDE INHIBITORS TO THERMOLYSIN DETERMINED BY X-RAY CRYSTALLOGRAPHY. A NOVEL CLASS OF TRANSITION-STATE ANALOGUES FOR ZINC PEPTIDASES'''<br /> | '''BINDING OF N-CARBOXYMETHYL DIPEPETIDE INHIBITORS TO THERMOLYSIN DETERMINED BY X-RAY CRYSTALLOGRAPHY. A NOVEL CLASS OF TRANSITION-STATE ANALOGUES FOR ZINC PEPTIDASES'''<br /> | ||
==Overview== | ==Overview== | ||
| - | The mode of binding of the specific thermolysin inhibitor | + | The mode of binding of the specific thermolysin inhibitor N-(1-carboxy-3-phenylpropyl)-L-leucyl-L-tryptophan (KI approximately 5 X 10(-8) M) [Maycock, A. L., DeSousa, D. M., Payne, L. G., ten Broeke, J., Wu, M. T., & Patchett, A. A. (1981) Biochem. Biophys. Res. Commun. 102, 963-969] has been determined by X-ray crystallography and refined to an R value of 17.1% at 1.9-A resolution. The inhibitor binds to thermolysin with both oxygens of the N-carboxymethyl group liganded to the zinc to give overall pentacoordination of the metal. The bidentate ligation of the inhibitor differs from the monodentate binding seen previously for carboxylate-zinc interactions in thermolysin and is closer to the bidentate geometry observed for the binding of hydroxamates [Holmes, M. A., & Matthews, B. W. (1981) Biochemistry 20, 6912-6920]. The geometry of the inhibitor and its interactions with the protein have a number of elements in common with the presumed transition state formed during peptide hydrolysis. The observed zinc ligation supports the previous suggestion that a pentacoordinate intermediate participates in the mechanism of catalysis. However, the alpha-amino nitrogen of the inhibitor is close to Glu-143, suggesting that this residue might accept a proton from an attacking water molecule (as proposed before) and subsequently donate this proton to the leaving nitrogen. By analogy with thermolysin, it is proposed that a related mechanism should be considered for peptide cleavage by carboxypeptidase A.(ABSTRACT TRUNCATED AT 250 WORDS) |
==About this Structure== | ==About this Structure== | ||
| - | 1TMN is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/ ] with CA and ZN as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Thermolysin Thermolysin], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.24.27 3.4.24.27] Full crystallographic information is available from [http:// | + | 1TMN is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/ ] with <scene name='pdbligand=CA:'>CA</scene> and <scene name='pdbligand=ZN:'>ZN</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Thermolysin Thermolysin], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.24.27 3.4.24.27] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1TMN OCA]. |
==Reference== | ==Reference== | ||
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[[Category: Single protein]] | [[Category: Single protein]] | ||
[[Category: Thermolysin]] | [[Category: Thermolysin]] | ||
| - | [[Category: Matthews, B | + | [[Category: Matthews, B W.]] |
| - | [[Category: Monzingo, A | + | [[Category: Monzingo, A F.]] |
[[Category: CA]] | [[Category: CA]] | ||
[[Category: ZN]] | [[Category: ZN]] | ||
[[Category: hydrolase (metalloproteinase)]] | [[Category: hydrolase (metalloproteinase)]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 15:15:11 2008'' |
Revision as of 13:15, 21 February 2008
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BINDING OF N-CARBOXYMETHYL DIPEPETIDE INHIBITORS TO THERMOLYSIN DETERMINED BY X-RAY CRYSTALLOGRAPHY. A NOVEL CLASS OF TRANSITION-STATE ANALOGUES FOR ZINC PEPTIDASES
Overview
The mode of binding of the specific thermolysin inhibitor N-(1-carboxy-3-phenylpropyl)-L-leucyl-L-tryptophan (KI approximately 5 X 10(-8) M) [Maycock, A. L., DeSousa, D. M., Payne, L. G., ten Broeke, J., Wu, M. T., & Patchett, A. A. (1981) Biochem. Biophys. Res. Commun. 102, 963-969] has been determined by X-ray crystallography and refined to an R value of 17.1% at 1.9-A resolution. The inhibitor binds to thermolysin with both oxygens of the N-carboxymethyl group liganded to the zinc to give overall pentacoordination of the metal. The bidentate ligation of the inhibitor differs from the monodentate binding seen previously for carboxylate-zinc interactions in thermolysin and is closer to the bidentate geometry observed for the binding of hydroxamates [Holmes, M. A., & Matthews, B. W. (1981) Biochemistry 20, 6912-6920]. The geometry of the inhibitor and its interactions with the protein have a number of elements in common with the presumed transition state formed during peptide hydrolysis. The observed zinc ligation supports the previous suggestion that a pentacoordinate intermediate participates in the mechanism of catalysis. However, the alpha-amino nitrogen of the inhibitor is close to Glu-143, suggesting that this residue might accept a proton from an attacking water molecule (as proposed before) and subsequently donate this proton to the leaving nitrogen. By analogy with thermolysin, it is proposed that a related mechanism should be considered for peptide cleavage by carboxypeptidase A.(ABSTRACT TRUNCATED AT 250 WORDS)
About this Structure
1TMN is a Single protein structure of sequence from [1] with and as ligands. Active as Thermolysin, with EC number 3.4.24.27 Full crystallographic information is available from OCA.
Reference
Binding of N-carboxymethyl dipeptide inhibitors to thermolysin determined by X-ray crystallography: a novel class of transition-state analogues for zinc peptidases., Monzingo AF, Matthews BW, Biochemistry. 1984 Nov 20;23(24):5724-9. PMID:6395881
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