1O5F

Dissecting and Designing Inhibitor Selectivity Determinants at the S1 site Using an Artificial Ala190 Protease (Ala190 uPA)


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.78 Å
  • R-Value Free: 0.231 
  • R-Value Work: 0.193 
  • R-Value Observed: 0.197 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.4 of the entry. See complete history


Literature

Dissecting and designing inhibitor selectivity determinants at the S1 site using an artificial Ala190 protease (Ala190 uPA).

Katz, B.A.Luong, C.Ho, J.D.Somoza, J.R.Gjerstad, E.Tang, J.Williams, S.R.Verner, E.Mackman, R.L.Young, W.B.Sprengeler, P.A.Chan, H.Mortara, K.Janc, J.W.McGrath, M.E.

(2004) J Mol Biol 344: 527-547

  • DOI: https://doi.org/10.1016/j.jmb.2004.09.032
  • Primary Citation of Related Structures:  
    1O5A, 1O5B, 1O5C, 1O5D, 1O5E, 1O5F, 1O5G

  • PubMed Abstract: 

    A site-directed mutant of the serine protease urokinase-type plasminogen activator (uPA), was produced to assess the contribution of the Ser190 side-chain to the affinity and selectivity of lead uPA inhibitors in the absence of other differences present in comparisons of natural proteases. Crystallography and enzymology involving WT and Ala190 uPA were used to calculate free energy binding contributions of hydrogen bonds involving the Ser190 hydroxyl group (O(gamma)(Ser190)) responsible for the remarkable selectivity of 6-halo-5-amidinoindole and 6-halo-5-amidinobenzimidazole inhibitors toward uPA and against natural Ala190 protease anti-targets. Crystal structures of uPA complexes of novel, active site-directed arylguanidine and 2-aminobenzimidazole inhibitors of WT uPA, together with associated K(i) values for WT and Ala190 uPA, also indicate a significant role of Ser190 in the binding of these classes of uPA inhibitors. Structures and associated K(i) values for a lead inhibitor (CA-11) bound to uPA and to five other proteases, as well as for other leads bound to multiple proteases, help reveal the features responsible for the potency (K(i)=11nM) and selectivity of the remarkably small inhibitor, CA-11. The 6-fluoro-5-amidinobenzimidzole, CA-11, is more than 1000-fold selective against natural Ala190 protease anti-targets, and more than 100-fold selective against other Ser190 anti-targets.


  • Organizational Affiliation

    Celera, 180 Kimball Way, South San Francisco, CA 94080, USA. brad.katz@celera.com


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Serine protease hepsinA [auth L]114Homo sapiensMutation(s): 1 
Gene Names: HPN OR TMPRSS1
EC: 3.4.21
UniProt & NIH Common Fund Data Resources
Find proteins for P05981 (Homo sapiens)
Explore P05981 
Go to UniProtKB:  P05981
PHAROS:  P05981
GTEx:  ENSG00000105707 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP05981
Sequence Annotations
Expand
  • Reference Sequence
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
Serine protease hepsinB [auth H]255Homo sapiensMutation(s): 0 
Gene Names: HPN OR TMPRSS1
EC: 3.4.21
UniProt & NIH Common Fund Data Resources
Find proteins for P05981 (Homo sapiens)
Explore P05981 
Go to UniProtKB:  P05981
PHAROS:  P05981
GTEx:  ENSG00000105707 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP05981
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
CR9
Query on CR9

Download Ideal Coordinates CCD File 
C [auth H]2-{5-[AMINO(IMINIO)METHYL]-6-FLUORO-1H-BENZIMIDAZOL-2-YL}-6-[(2-METHYLCYCLOHEXYL)OXY]BENZENOLATE
C21 H23 F N4 O2
CMCDWLMEDRBWIR-GTNSWQLSSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
CR9 BindingDB:  1O5F Ki: 850 (nM) from 1 assay(s)
PDBBind:  1O5F Ki: 850 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.78 Å
  • R-Value Free: 0.231 
  • R-Value Work: 0.193 
  • R-Value Observed: 0.197 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 59.02α = 90
b = 47.95β = 105.23
c = 63.38γ = 90
Software Package:
Software NamePurpose
CrystalCleardata collection
CrystalCleardata reduction
X-PLORrefinement
CrystalCleardata scaling
Quantamodel building

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Revision History  (Full details and data files)

  • Version 1.0: 2004-09-21
    Type: Initial release
  • Version 1.1: 2007-10-21
    Changes: Version format compliance
  • Version 1.2: 2011-07-13
    Changes: Version format compliance
  • Version 1.3: 2021-10-27
    Changes: Database references, Derived calculations
  • Version 1.4: 2023-12-27
    Changes: Data collection