1C2I

RECRUITING ZINC TO MEDIATE POTENT, SPECIFIC INHIBITION OF SERINE PROTEASES


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.47 Å
  • R-Value Free: 0.208 
  • R-Value Work: 0.177 
  • R-Value Observed: 0.177 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.4 of the entry. See complete history


Literature

Design of potent selective zinc-mediated serine protease inhibitors.

Katz, B.A.Clark, J.M.Finer-Moore, J.S.Jenkins, T.E.Johnson, C.R.Ross, M.J.Luong, C.Moore, W.R.Stroud, R.M.

(1998) Nature 391: 608-612

  • DOI: https://doi.org/10.1038/35422
  • Primary Citation of Related Structures:  
    1C1N, 1C1O, 1C1P, 1C1Q, 1C1R, 1C1T, 1C1U, 1C1V, 1C1W, 1C2D, 1C2E, 1C2F, 1C2G, 1C2H, 1C2I, 1C2J, 1C2K, 1C2L, 1C2M, 1XUF, 1XUG, 1XUH, 1XUI, 1XUJ, 1XUK

  • PubMed Abstract: 

    Many serine proteases are targets for therapeutic intervention because they often play key roles in disease. Small molecule inhibitors of serine proteases with high affinity are especially interesting as they could be used as scaffolds from which to develop drugs selective for protease targets. One such inhibitor is bis(5-amidino-2-benzimidazolyl)methane (BABIM), standing out as the best inhibitor of trypsin (by a factor of over 100) in a series of over 60 relatively closely related analogues. By probing the structural basis of inhibition, we discovered, using crystallographic methods, a new mode of high-affinity binding in which a Zn2+ ion is tetrahedrally coordinated between two chelating nitrogens of BABIM and two active site residues, His57 and Ser 195. Zn2+, at subphysiological levels, enhances inhibition by over 10(3)-fold. The distinct Zn2+ coordination geometry implies a strong dependence of affinity on substituents. This unique structural paradigm has enabled development of potent, highly selective, Zn2+-dependent inhibitors of several therapeutically important serine proteases, using a physiologically ubiquitous metal ion.


  • Organizational Affiliation

    Arris Pharmaceutical Corporation, South San Francisco, California 94080, USA. bak@arris.com


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
TRYPSIN223Bos taurusMutation(s): 0 
EC: 3.4.21.4
UniProt
Find proteins for P00760 (Bos taurus)
Explore P00760 
Go to UniProtKB:  P00760
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP00760
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 5 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
BAK
Query on BAK

Download Ideal Coordinates CCD File 
G [auth A]BIS(5-AMIDINO-2-BENZIMIDAZOLYL)METHANE KETONE
C17 H16 N8 O
VVVXDHROXQUONB-UHFFFAOYSA-P
DMS
Query on DMS

Download Ideal Coordinates CCD File 
H [auth A]DIMETHYL SULFOXIDE
C2 H6 O S
IAZDPXIOMUYVGZ-UHFFFAOYSA-N
ZN
Query on ZN

Download Ideal Coordinates CCD File 
D [auth A],
E [auth A],
F [auth A]
ZINC ION
Zn
PTFCDOFLOPIGGS-UHFFFAOYSA-N
CA
Query on CA

Download Ideal Coordinates CCD File 
B [auth A]CALCIUM ION
Ca
BHPQYMZQTOCNFJ-UHFFFAOYSA-N
CL
Query on CL

Download Ideal Coordinates CCD File 
C [auth A]CHLORIDE ION
Cl
VEXZGXHMUGYJMC-UHFFFAOYSA-M
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.47 Å
  • R-Value Free: 0.208 
  • R-Value Work: 0.177 
  • R-Value Observed: 0.177 
  • Space Group: P 31 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 55α = 90
b = 55β = 90
c = 109.76γ = 120
Software Package:
Software NamePurpose
bioteXdata collection
bioteXdata reduction
X-PLORmodel building
Quantamodel building
Insight IImodel building
X-PLORrefinement
bioteXdata scaling
X-PLORphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2000-07-26
    Type: Initial release
  • Version 1.1: 2008-04-26
    Changes: Version format compliance
  • Version 1.2: 2011-07-13
    Changes: Version format compliance
  • Version 1.3: 2017-10-04
    Changes: Advisory, Refinement description
  • Version 1.4: 2023-12-27
    Changes: Advisory, Data collection, Database references, Derived calculations