2V35

Porcine Pancreatic Elastase in complex with inhibitor JM54

Summary for 2V35

• Entry DOI: 10.2210/pdb2v35/pdb
• 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
• Descriptor: ELASTASE-1, (2R)-3-{[(BENZYLAMINO)CARBONYL]AMINO}-2-HYDROXYPROPANOIC ACID, SODIUM ION, ... (6 entities in total)
• Functional Keywords: serine protease, serine proteases, calcium, zymogen, protease, elastase, hydrolase, inhibition, beta-lactams, metal-binding
• Biological source: SUS SCROFA (PIG)
• Total number of polymer chains: 1
• Total formula weight: 26470.50

Authors

Oliveira, T.F.,Mulchande, J.,Martins, L.,Moreira, R.,Iley, J.,Archer, M. (deposition date: 2007-06-12, release date: 2008-06-24, Last modification date: 2023-12-13)

Primary citation

Mulchande, J.,Martins, L.,Moreira, R.,Archer, M.,Oliveira, T.F.,Iley, J.
The Efficiency of C-4 Substituents in Activating the Beta-Lactam Scaffold Towards Serine Proteases and Hydroxide Ion.
Org.Biomol.Chem., 5:2617-, 2007

PubMed Abstract: 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.

PubMed: 18019537
DOI: 10.1039/B706622H

Experimental method

X-RAY DIFFRACTION (1.67 Å)