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1ppm
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'''CRYSTALLOGRAPHIC ANALYSIS OF TRANSITION-STATE MIMICS BOUND TO PENICILLOPEPSIN: PHOSPHORUS-CONTAINING PEPTIDE ANALOGUES''' | '''CRYSTALLOGRAPHIC ANALYSIS OF TRANSITION-STATE MIMICS BOUND TO PENICILLOPEPSIN: PHOSPHORUS-CONTAINING PEPTIDE ANALOGUES''' | ||
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==About this Structure== | ==About this Structure== | ||
| - | 1PPM is a [[Single protein]] structure | + | 1PPM is a [[Single protein]] structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1PPM OCA]. |
==Reference== | ==Reference== | ||
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[[Category: Fraser, M E.]] | [[Category: Fraser, M E.]] | ||
[[Category: James, M N.G.]] | [[Category: James, M N.G.]] | ||
| - | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sat May 3 05:20:33 2008'' | |
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Revision as of 02:20, 3 May 2008
CRYSTALLOGRAPHIC ANALYSIS OF TRANSITION-STATE MIMICS BOUND TO PENICILLOPEPSIN: PHOSPHORUS-CONTAINING PEPTIDE ANALOGUES
Overview
The molecular structures of three phosphorus-based peptide inhibitors of aspartyl proteinases complexed with penicillopepsin [1, Iva-L-Val-L-Val-StaPOEt [Iva = isovaleryl, StaP = the phosphinic acid analogue of statine [(S)-4-amino-(S)-3-hydroxy-6-methylheptanoic acid] (IvaVVStaPOEt)]; 2, Iva-L-Val-L-Val-L-LeuP-(O)Phe-OMe [LeuP = the phosphinic acid analogue of L-leucine; (O)Phe = L-3-phenyllactic acid; OMe = methyl ester] [Iva VVLP(O)FOMe]; and 3, Cbz-L-Ala-L-Ala-L-LeuP-(O)-Phe-OMe (Cbz = benzyloxycarbonyl) [CbzAALP(O)FOMe]] have been determined by X-ray crystallography and refined to crystallographic agreement factors, R ( = sigma parallel to F0 magnitude of - Fc parallel to/sigma magnitude of F0), of 0.132, 0.131, and 0.134, respectively. These inhibitors were designed to be structural mimics of the tetrahederal transition-state intermediate encountered during aspartic proteinase catalysis. They are potent inhibitors of penicillopepsin with Ki values of 1, 22 nM; 2, 2.8 nM; and 3, 1600 nM, respectively [Bartlett, P. A., Hanson, J. E., & Giannousis, P. P. (1990) J. Org. Chem. 55, 6268-6274]. All three of these phosphorus-based inhibitors bind virtually identically in the active site of penicillopepsin in a manner that closely approximates that expected for the transition state [James, M. N. G., Sielecki, A.R., Hayakawa, K., & Gelb, M. H. (1992) Biochemistry 31, 3872-3886]. The pro-S oxygen atom of the two phosphonate inhibitors and of the phosphinate group of the StaP inhibitor make very short contact distances (approximately 2.4 A) to the carboxyl oxygen atom, O delta 1, of Asp33 on penicillopepsin. We have interpreted this distance and the stereochemical environment of the carboxyl and phosphonate groups in terms of a hydrogen bond that most probably has a symmetric single-well potential energy function. The pro-R oxygen atom is the recipient of a hydrogen bond from the carboxyl group of Asp213. Thus, we are able to assign a neutral status to Asp213 and a partially negatively charged status to Asp33 with reasonable confidence. Similar very short hydrogen bonds involving the active site glutamic acid residues of thermolysin and carboxypeptidase A and the pro-R oxygen of bound phosphonate inhibitors have been reported [Holden, H. M., Tronrud, D. E., Monzingo, A. F., Weaver, L. H., & Matthews, B. W. (1987) Biochemistry 26, 8542-8553; Kim, H., & Lipscomb, W. N. (1991) Biochemistry 30, 8171-8180].(ABSTRACT TRUNCATED AT 400 WORDS)
About this Structure
1PPM is a Single protein structure. Full crystallographic information is available from OCA.
Reference
Crystallographic analysis of transition-state mimics bound to penicillopepsin: phosphorus-containing peptide analogues., Fraser ME, Strynadka NC, Bartlett PA, Hanson JE, James MN, Biochemistry. 1992 Jun 9;31(22):5201-14. PMID:1606144 Page seeded by OCA on Sat May 3 05:20:33 2008
