2H5S

SA2-13 penam sulfone complexed to wt SHV-1 beta-lactamase


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.28 Å
  • R-Value Free: 0.167 
  • R-Value Work: 0.154 
  • R-Value Observed: 0.154 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.4 of the entry. See complete history


Literature

Rational Design of a beta-Lactamase Inhibitor Achieved via Stabilization of the trans-Enamine Intermediate: 1.28 A Crystal Structure of wt SHV-1 Complex with a Penam Sulfone.

Padayatti, P.S.Sheri, A.Totir, M.A.Helfand, M.S.Carey, M.P.Anderson, V.E.Carey, P.R.Bethel, C.R.Bonomo, R.A.Buynak, J.D.van den Akker, F.

(2006) J Am Chem Soc 128: 13235-13242

  • DOI: https://doi.org/10.1021/ja063715w
  • Primary Citation of Related Structures:  
    2H5S

  • PubMed Abstract: 

    beta-Lactamases are one of the major causes of antibiotic resistance in Gram negative bacteria. The continuing evolution of beta-lactamases that are capable of hydrolyzing our most potent beta-lactams presents a vexing clinical problem, in particular since a number of them are resistant to inhibitors. The efficient inhibition of these enzymes is therefore of great clinical importance. Building upon our previous structural studies that examined tazobactam trapped as a trans-enamine intermediate in a deacylation deficient SHV variant, we designed a novel penam sulfone derivative that forms a more stable trans-enamine intermediate. We report here the 1.28 A resolution crystal structure of wt SHV-1 in complex with a rationally designed penam sulfone, SA2-13. The compound is covalently bound to the active site of wt SHV-1 similar to tazobactam yet forms an additional salt-bridge with K234 and hydrogen bonds with S130 and T235 to stabilize the trans-enamine intermediate. Kinetic measurements show that SA2-13, once reacted with SHV-1 beta-lactamase, is about 10-fold slower at being released from the enzyme compared to tazobactam. Stabilizing the trans-enamine intermediate represents a novel strategy for the rational design of mechanism-based class A beta-lactamase inhibitors.


  • Organizational Affiliation

    Department of Biochemistry, Case Western Reserve University, Cleveland, Ohio 44106, USA.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
SHV-1 beta-lactamase265Klebsiella pneumoniaeMutation(s): 0 
EC: 3.5.2.6
UniProt
Find proteins for P0AD64 (Klebsiella pneumoniae)
Explore P0AD64 
Go to UniProtKB:  P0AD64
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP0AD64
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 2 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
MA4
Query on MA4

Download Ideal Coordinates CCD File 
C [auth A],
D [auth A]
CYCLOHEXYL-HEXYL-BETA-D-MALTOSIDE
C24 H44 O11
WUCWJXGMSXTDAV-QKMCSOCLSA-N
SA2
Query on SA2

Download Ideal Coordinates CCD File 
B [auth A](3R)-4-[(4-CARBOXYBUTANOYL)OXY]-N-[(1E)-3-OXOPROP-1-EN-1-YL]-3-SULFINO-D-VALINE
C13 H19 N O9 S
ZLJAMSCQNNEARN-QDZHIHTESA-N
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.28 Å
  • R-Value Free: 0.167 
  • R-Value Work: 0.154 
  • R-Value Observed: 0.154 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 49.81α = 90
b = 55.22β = 90
c = 84.43γ = 90
Software Package:
Software NamePurpose
CNSrefinement
HKL-2000data scaling
CNSphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2006-10-17
    Type: Initial release
  • Version 1.1: 2008-05-01
    Changes: Version format compliance
  • Version 1.2: 2011-07-13
    Changes: Version format compliance
  • Version 1.3: 2017-10-18
    Changes: Refinement description
  • Version 1.4: 2023-08-30
    Changes: Data collection, Database references, Derived calculations, Refinement description