pKaAnalysis for the Zinc-Bound Water in Human Carbonic Anhydrase II:  Benchmark for “Multiscale” QM/MM Simulations and Mechanistic Implications†

2007 ◽  
Vol 111 (26) ◽  
pp. 5703-5711 ◽  
Author(s):  
Demian Riccardi ◽  
Qiang Cui
Keyword(s):  
Carbonic Anhydrase ◽  
Bound Water ◽  
Carbonic Anhydrase Ii ◽  
Human Carbonic Anhydrase

scholarly journals Positions of His-64 and a bound water in human carbonic anhydrase II upon binding three structurally related inhibitors

1994 ◽  
Vol 3 (1) ◽  
pp. 118-125 ◽  
Author(s):  
Graham M. Smith ◽  
Richard S Alexander ◽  
David W. Christianson ◽  
Brian M. Mckeever ◽  
Gerald S. Ponticello ◽  
...  
Keyword(s):  
Carbonic Anhydrase ◽  
Bound Water ◽  
Carbonic Anhydrase Ii ◽  
Human Carbonic Anhydrase

scholarly journals Active-site solvent replenishment observed during human carbonic anhydrase II catalysis

IUCrJ ◽  
2018 ◽  
Vol 5 (1) ◽  
pp. 93-102 ◽  
Author(s):  
Jin Kyun Kim ◽  
Carrie L. Lomelino ◽  
Balendu Sankara Avvaru ◽  
Brian P. Mahon ◽  
Robert McKenna ◽  
...  
Keyword(s):  
Carbonic Anhydrase ◽  
Proton Transfer ◽  
Active Site ◽  
Water Reservoir ◽  
Bound Water ◽  
Nucleophilic Attack ◽  
Carbonic Anhydrase Ii ◽  
Intermediate Water ◽  
Water Network ◽  
Human Carbonic Anhydrase

Human carbonic anhydrase II (hCA II) is a zinc metalloenzyme that catalyzes the reversible hydration/dehydration of CO2/HCO3 −. Although hCA II has been extensively studied to investigate the proton-transfer process that occurs in the active site, its underlying mechanism is still not fully understood. Here, ultrahigh-resolution crystallographic structures of hCA II cryocooled under CO2 pressures of 7.0 and 2.5 atm are presented. The structures reveal new intermediate solvent states of hCA II that provide crystallographic snapshots during the restoration of the proton-transfer water network in the active site. Specifically, a new intermediate water (WI′) is observed next to the previously observed intermediate water WI, and they are both stabilized by the five water molecules at the entrance to the active site (the entrance conduit). Based on these structures, a water network-restructuring mechanism is proposed, which takes place at the active site after the nucleophilic attack of OH− on CO2. This mechanism explains how the zinc-bound water (WZn) and W1 are replenished, which are directly responsible for the reconnection of the His64-mediated proton-transfer water network. This study provides the first `physical' glimpse of how a water reservoir flows into the hCA II active site during its catalytic activity.

Crystal structure of human carbonic anhydrase II complexed with ananti-convulsant sugar sulphamate

2002 ◽  
Vol 361 (3) ◽  
pp. 437-441 ◽  
Author(s):  
Rosario RECACHA ◽  
Michael J. COSTANZO ◽  
Bruce E. MARYANOFF ◽  
Debasish CHATTOPADHYAY
Keyword(s):  
Carbonic Anhydrase ◽  
Oxygen Atom ◽  
Active Site ◽  
Enzyme Inhibitor ◽  
Bound Water ◽  
Zinc Ion ◽  
Carbonic Anhydrase Ii ◽  
Sulphate Group ◽  
X Ray Crystallography ◽  
Human Carbonic Anhydrase

The fructose-based sugar sulphamate RWJ-37497, a potent analogue of the widely used anti-epileptic drug topiramate, possesses anti-convulsant and carbonic anhydrase-inhibitory activities. We have studied the binding interactions of RWJ-37497 in the active site of human carbonic anhydrase II by X-ray crystallography. The atomic positions of the enzyme inhibitor complex were refined at a resolution of 2.1 Å (1 Å = 0.1 nm) to the final crystallographic R and Rfree values of 0.18 and 0.23, respectively. The inhibitor co-ordinates to the active-site zinc ion through its oxygen atom and the ionized nitrogen atom of the sulphamate group by replacing the metal-bound water molecules, although the sulphamoyl oxygen atom provides a rather lengthyco-ordination. The 4,5-cyclic sulphate group is positioned in a hydrophobic pocket of the active site, making contacts with the residues Phe-131, Leu-198, Pro-201 and Pro-202. Since the ligand was found to be intact, concerns about RWJ-37947 irreversibly alkylating the enzyme through its 4,5-cyclic sulphate group were dispelled.

scholarly journals The Influence of Varying Fluorination Patterns on the Thermodynamics and Kinetics of Benzenesulfonamide Binding to Human Carbonic Anhydrase II

Biomolecules ◽  
2020 ◽  
Vol 10 (4) ◽  
pp. 509 ◽  
Author(s):  
Steffen Glöckner ◽  
Khang Ngo ◽  
Björn Wagner ◽  
Andreas Heine ◽  
Gerhard Klebe
Keyword(s):  
Carbonic Anhydrase ◽  
Carbonic Anhydrase Ii ◽  
The Novel ◽  
Binding Modes ◽  
X Ray ◽  
Structure Activity ◽  
Small Set ◽  
Novel Method ◽  
Human Carbonic Anhydrase ◽  
Kinetics Of

The fluorination of lead-like compounds is a common tool in medicinal chemistry to alter molecular properties in various ways and with different goals. We herein present a detailed study of the binding of fluorinated benzenesulfonamides to human Carbonic Anhydrase II by complementing macromolecular X-ray crystallographic observations with thermodynamic and kinetic data collected with the novel method of kinITC. Our findings comprise so far unknown alternative binding modes in the crystalline state for some of the investigated compounds as well as complex thermodynamic and kinetic structure-activity relationships. They suggest that fluorination of the benzenesulfonamide core is especially advantageous in one position with respect to the kinetic signatures of binding and that a higher degree of fluorination does not necessarily provide for a higher affinity or more favorable kinetic binding profiles. Lastly, we propose a relationship between the kinetics of binding and ligand acidity based on a small set of compounds with similar substitution patterns.

Salt mediated unusual switching in the aggregation kinetic profile of human carbonic anhydrase

RSC Advances ◽  
2015 ◽  
Vol 5 (116) ◽  
pp. 95717-95726 ◽  
Author(s):  
Preeti Gupta ◽  
Shashank Deep
Keyword(s):  
Carbonic Anhydrase ◽  
Carbonic Anhydrase Ii ◽  
Aggregation Kinetic ◽  
Kinetic Profile ◽  
Human Carbonic Anhydrase

Aggregation pathway of human carbonic anhydrase II in the presence of salt.

Sign in / Sign up

Export Citation Format

Share Document