Binding modes for substrate and a proposed transition-state analog of protozoan nucleoside hydrolase

Biochemistry ◽  
1995 ◽  
Vol 34 (42) ◽  
pp. 13961-13966 ◽  
Author(s):  
David W. Parkin ◽  
Vern L. Schramm
Keyword(s):  
Transition State ◽  
Binding Modes ◽  
Transition State Analog ◽  
Nucleoside Hydrolase

scholarly journals Crystal Structures of KPC-2 and SHV-1 β-Lactamases in Complex with the Boronic Acid Transition State Analog S02030

2016 ◽  
Vol 60 (3) ◽  
pp. 1760-1766 ◽  
Author(s):  
Nhu Q. Nguyen ◽  
Nikhil P. Krishnan ◽  
Laura J. Rojas ◽  
Fabio Prati ◽  
Emilia Caselli ◽  
...  
Keyword(s):  
Transition State ◽  
Crystal Structures ◽  
Boronic Acid ◽  
Active Sites ◽  
Triazole Ring ◽  
Binding Modes ◽  
Content Type ◽  
Transition State Analog ◽  
Broad Spectrum Resistance ◽  
Thiophene Moiety

Resistance to expanded-spectrum cephalosporins and carbapenems has rendered certain strains ofKlebsiella pneumoniaethe most problematic pathogens infecting patients in the hospital and community. This broad-spectrum resistance to β-lactamases emerges in part via the expression of KPC-2 and SHV-1 β-lactamases and variants thereof. KPC-2 carbapenemase is particularly worrisome, as the genetic determinant encoding this β-lactamase is rapidly spread via plasmids. Moreover, KPC-2, a class A enzyme, is difficult to inhibit with mechanism-based inactivators (e.g., clavulanate). In order to develop new β-lactamase inhibitors (BLIs) to add to the limited available armamentarium that can inhibit KPC-2, we have structurally probed the boronic acid transition state analog S02030 for its inhibition of KPC-2 and SHV-1. S02030 contains a boronic acid, a thiophene, and a carboxyl triazole moiety. We present here the 1.54- and 1.87-Å resolution crystal structures of S02030 bound to SHV-1 and KPC-2 β-lactamases, respectively, as well as a comparative analysis of the S02030 binding modes, including a previously determined S02030 class C ADC-7 β-lactamase complex. S02030 is able to inhibit vastly different serine β-lactamases by interacting with the conserved features of these active sites, which includes (i) forming the bond with catalytic serine via the boron atom, (ii) positioning one of the boronic acid oxygens in the oxyanion hole, and (iii) utilizing its amide moiety to make conserved interactions across the width of the active site. In addition, S02030 is able to overcome more distantly located structural differences between the β-lactamases. This unique feature is achieved by repositioning the more polar carboxyl-triazole moiety, generated by click chemistry, to create polar interactions as well as reorient the more hydrophobic thiophene moiety. The former is aided by the unusual polar nature of the triazole ring, allowing it to potentially form a unique C—H…O 2.9-Å hydrogen bond with S130 in KPC-2.

scholarly journals Beef heart mitochondrial adenosine triphosphatase-catalyzed formation of a transition state analog in ATP synthesis.

1980 ◽  
Vol 255 (11) ◽  
pp. 5342-5346
Author(s):  
M.J. Bossard ◽  
T.A. Vik ◽  
S.M. Schuster
Keyword(s):  
Transition State ◽  
Adenosine Triphosphatase ◽  
Atp Synthesis ◽  
Beef Heart ◽  
Transition State Analog

Renin inhibitors. Synthesis of transition-state analog inhibitors containing phosphorus acid derivatives at the scissile bond

1989 ◽  
Vol 32 (7) ◽  
pp. 1652-1661 ◽  
Author(s):  
Mark C. Allen ◽  
Walter Fuhrer ◽  
Brian Tuck ◽  
Roy Wade ◽  
Jeanette M. Wood
Keyword(s):  
Transition State ◽  
Phosphorus Acid ◽  
Transition State Analog ◽  
Renin Inhibitors ◽  
Scissile Bond

scholarly journals A crystallographic study of the Toho-1 β-lactamase acylation mechanism

2014 ◽  
Vol 70 (a1) ◽  
pp. C1207-C1207
Author(s):  
Leighton Coates
Keyword(s):  
Hydrogen Bonding ◽  
Transition State ◽  
Active Site ◽  
Catalytic Mechanism ◽  
Substrate Binding ◽  
Ligand Complex ◽  
Transition State Analog ◽  
Hydrogen Bonding Interactions ◽  
Active Site Region ◽  
Neutron Crystallography

β-lactam antibiotics have been used effectively over several decades against many types of highly virulent bacteria. The predominant cause of resistance to these antibiotics in Gram-negative bacterial pathogens is the production of serine β-lactamase enzymes. A key aspect of the class A serine β-lactamase mechanism that remains unresolved and controversial is the identity of the residue acting as the catalytic base during the acylation reaction. Multiple mechanisms have been proposed for the formation of the acyl-enzyme intermediate that are predicated on understanding the protonation states and hydrogen-bonding interactions among the important residues involved in substrate binding and catalysis of these enzymes. For resolving a controversy of this nature surrounding the catalytic mechanism, neutron crystallography is a powerful complement to X-ray crystallography that can explicitly determine the location of deuterium atoms in proteins, thereby directly revealing the hydrogen-bonding interactions of important amino acid residues. Neutron crystallography was used to unambiguously reveal the ground-state active site protonation states and the resulting hydrogen-bonding network in two ligand-free Toho-1 β-lactamase mutants which provided remarkably clear pictures of the active site region prior to substrate binding and subsequent acylation [1,2] and an acylation transition-state analog, benzothiophene-2-boronic acid (BZB), which was also isotopically enriched with 11B. The neutron structure revealed the locations of all deuterium atoms in the active site region and clearly indicated that Glu166 is protonated in the BZB transition-state analog complex. As a result, the complete hydrogen-bonding pathway throughout the active site region could then deduced for this protein-ligand complex that mimics the acylation tetrahedral intermediate [3].

Crystal Structure of Bovine Low Molecular Weight Phosphotyrosyl Phosphatase Complexed with the Transition State Analog Vanadate†,‡

Biochemistry ◽  
1997 ◽  
Vol 36 (1) ◽  
pp. 15-23 ◽  
Author(s):  
Marie Zhang ◽  
Ming Zhou ◽  
Robert L. Van Etten ◽  
Cynthia V. Stauffacher
Keyword(s):  
Crystal Structure ◽  
Molecular Weight ◽  
Transition State ◽  
Low Molecular Weight ◽  
Transition State Analog

Phosphonamidates as transition-state analog inhibitors of thermolysin

Biochemistry ◽  
1983 ◽  
Vol 22 (20) ◽  
pp. 4618-4624 ◽  
Author(s):  
Paul A. Bartlett ◽  
Charles K. Marlowe
Keyword(s):  
Transition State ◽  
Transition State Analog
Sign in / Sign up

Export Citation Format

Share Document