| Structural highlights
2v35 is a 1 chain structure with sequence from Sus scrofa. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Ligands: | , , ,
| | Related: | 1b0e, 1bma, 1btu, 1c1m, 1e34, 1e35, 1e36, 1e37, 1e38, 1eai, 1eas, 1eat, 1eau, 1ela, 1elb, 1elc, 1eld, 1ele, 1elf, 1elg, 1esa, 1esb, 1est, 1fle, 1fzz, 1gvk, 1gwa, 1h9l, 1hax, 1hay, 1haz, 1hb0, 1hv7, 1inc, 1jim, 1l0z, 1l1g, 1lka, 1lkb, 1lvy, 1mcv, 1mmj, 1nes, 1okx, 1qgf, 1qix, 1qnj, 1qr3, 1uo6, 1uvo, 1uvp, 2a7c, 2a7j, 2blo, 2blq, 2cv3, 2d26, 2de8, 2de9, 2est, 2h1u, 2v0b, 3est, 4est, 5est, 6est, 7est, 8est, 9est |
| Activity: | Pancreatic elastase, with EC number 3.4.21.36 |
| Resources: | FirstGlance, OCA, RCSB, PDBsum |
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
The presence of a leaving group at C-4 of monobactams is usually considered to be a requirement for mechanism-based inhibition of human leukocyte elastase by these acylating agents. We report that second-order rate constants for the alkaline hydrolysis and elastase inactivation by N-carbamoyl monobactams are independent of the pKa of the leaving group at C-4. Indeed, the effect exerted by these substituents is purely inductive: electron-withdrawing substituents at C-4 of N-carbamoyl-3,3-diethylmonobactams increase the rate of alkaline hydrolysis and elastase inactivation, with Hammett pI values of 3.4 and 2.5, respectively, which indicate the development of a negative charge in the transition-states. The difference in magnitude between these pI values is consistent with an earlier transition-state for the enzymatic reaction when compared with that for the chemical process. These results suggest that the rate-limiting step in elastase inactivation is the formation of the tetrahedral intermediate, and that beta-lactam ring-opening is not concerted with the departure of a leaving group from C-4. Monobactam sulfones emerged as potent elastase inhibitors even when the ethyl groups at C-3, required for interaction with the primary recognition site, are absent. For one such compound, a 1 : 1 enzyme-inhibitor complex involving porcine pancreatic elastase has been examined by X-ray crystallography and shown to result from serine acylation and sulfinate departure from the beta-lactam C-4.
The efficiency of C-4 substituents in activating the beta-lactam scaffold towards serine proteases and hydroxide ion.,Mulchande J, Martins L, Moreira R, Archer M, Oliveira TF, Iley J Org Biomol Chem. 2007 Aug 21;5(16):2617-26. PMID:18019537[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Mulchande J, Martins L, Moreira R, Archer M, Oliveira TF, Iley J. The efficiency of C-4 substituents in activating the beta-lactam scaffold towards serine proteases and hydroxide ion. Org Biomol Chem. 2007 Aug 21;5(16):2617-26. PMID:18019537
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