1YYY

Trypsin inhibitors with rigid tripeptidyl aldehydes


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.10 Å
  • R-Value Work: 0.157 

wwPDB Validation   3D Report Full Report


This is version 1.4 of the entry. See complete history


Literature

Highly selective mechanism-based thrombin inhibitors: structures of thrombin and trypsin inhibited with rigid peptidyl aldehydes.

Krishnan, R.Zhang, E.Hakansson, K.Arni, R.K.Tulinsky, A.Lim-Wilby, M.S.Levy, O.E.Semple, J.E.Brunck, T.K.

(1998) Biochemistry 37: 12094-12103

  • DOI: https://doi.org/10.1021/bi980840e
  • Primary Citation of Related Structures:  
    1BA8, 1BB0, 1CA8, 1YYY, 1ZZZ

  • PubMed Abstract: 

    The crystal structures of three highly potent and selective low-molecular weight rigid peptidyl aldehyde inhibitors complexed with thrombin have been determined and refined to R values 0.152-0. 170 at 1.8-2.1 A resolution. Since the selectivity of two of the inhibitors was >1600 with respect to trypsin, the structures of trypsin-inhibited complexes of these inhibitors were also determined (R = 0.142-0.157 at 1.9-2.1 A resolution). The selectivity appears to reside in the inability of a benzenesulfonamide group to bind at the equivalent of the D-enantiomorphic S3 site of thrombin, which may be related to the lack of a 60-insertion loop in trypsin. All the inhibitors have a novel lactam moiety at the P3 position, while the two with greatest trypsin selectivity have a guanidinopiperidyl group at the P1 position that binds in the S1 specificity site. Differences in the binding constants of these inhibitors are correlated with their interactions with thrombin and trypsin. The kinetics of inhibition vary from slow to fast with thrombin and are fast in all cases with trypsin. The kinetics are examined in terms of the slow formation of a stable transition-state complex in a two-step mechanism. The structures of both thrombin and trypsin complexes show similar well-defined transition states in the S1 site and at the electrophilic carbon atom and Ser195OG. The trypsin structures, however, suggest that the first step in a two-step kinetic mechanism may involve formation of a weak transition-state complex, rather than binding dominated by the P2-P4 positions.


  • Organizational Affiliation

    Corvas International Inc., San Diego, California 92121, USA.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
TRYPSINA [auth 1]223Bos 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 2 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
0KV
Query on 0KV

Download Ideal Coordinates CCD File 
C [auth 1]2-{(3S)-3-[(benzylsulfonyl)amino]-2-oxopiperidin-1-yl}-N-{(2S)-1-[(3S)-1-carbamimidoylpiperidin-3-yl]-3-oxopropan-2-yl}acetamide
C23 H34 N6 O5 S
DATYERRDSFNBDN-UFYCRDLUSA-N
CA
Query on CA

Download Ideal Coordinates CCD File 
B [auth 1]CALCIUM ION
Ca
BHPQYMZQTOCNFJ-UHFFFAOYSA-N
Biologically Interesting Molecules (External Reference) 1 Unique
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.10 Å
  • R-Value Work: 0.157 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 63.76α = 90
b = 63.14β = 90
c = 69.29γ = 90
Software Package:
Software NamePurpose
R-AXISdata collection
R-AXISdata reduction
X-PLORmodel building
PROFFTrefinement
X-PLORrefinement
R-AXISdata scaling
X-PLORphasing

Structure Validation

View Full Validation Report



Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 1999-06-08
    Type: Initial release
  • Version 1.1: 2008-03-24
    Changes: Version format compliance
  • Version 1.2: 2011-07-13
    Changes: Atomic model, Database references, Derived calculations, Non-polymer description, Structure summary, Version format compliance
  • Version 1.3: 2012-12-12
    Changes: Other
  • Version 1.4: 2023-08-09
    Changes: Database references, Derived calculations, Other, Refinement description