2A2X

Orally Active Thrombin Inhibitors in Complex with Thrombin Inh12

PDB DOI: https://doi.org/10.2210/pdb2A2X/pdb

Classification: HYDROLASE/HYDROLASE INHIBITOR
Organism(s): Homo sapiens
Mutation(s): No

Deposited: 2005-06-23 Released: 2006-11-14
Deposition Author(s): Lange, U.E.W., Baucke, D., Hornberger, W., Mack, H., Seitz, W., Hoeffken, H.W.

Experimental Data Snapshot

Method: X-RAY DIFFRACTION
Resolution: 2.44 Å
R-Value Free: 0.221
R-Value Work: 0.198

wwPDB Validation 3D Report Full Report

Ligand Structure Quality Assessment

This is version 1.6 of the entry. See complete history.

Literature

Orally active thrombin inhibitors. Part 2: optimization of the P2-moiety

Lange, U.E.W., Baucke, D., Hornberger, W., Mack, H., Seitz, W., Hoeffken, H.W.

(2006) Bioorg Med Chem Lett 16: 2648-2653

PubMed: 16460939 Search on PubMed
DOI: https://doi.org/10.1016/j.bmcl.2006.01.046
Primary Citation of Related Structures:
2A2X, 2ANK, 2ANM

PubMed Abstract:
Synthesis and SAR of orally active thrombin inhibitors of the d-Phe-Pro-Arg type with focus on the P2-moiety are described. The unexpected increase in in vitro potency, oral bioavailability, and in vivo activity of inhibitors with dehydroproline as P2-isostere is discussed. Over a period of 24h the antithrombin activity of the most active inhibitors with IC(50)s in the nanomolar range was determined in dogs demonstrating high thrombin inhibitory activity in plasma and an appropriate duration of action after oral administration.

Organizational Affiliation

Abbott GmbH & Co. KG, D-67061 Ludwigshafen, Germany. udo.lange@abbott.com

Macromolecule Content

Total Structure Weight: 35.59 kDa
Atom Count: 2,606
Modelled Residue Count: 295
Deposited Residue Count: 304
Unique protein chains: 3

Macromolecules

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(by identity cutoff) | 3D Structure

Entity ID: 1
Molecule	Chains	Sequence Length	Organism	Details	Image
Thrombin light chain	A [auth L]	34	Homo sapiens	Mutation(s): 0
UniProt & NIH Common Fund Data Resources
Find proteins for P00734 (Homo sapiens) Explore P00734 Go to UniProtKB: P00734
PHAROS: P00734 GTEx: ENSG00000180210
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt Group	P00734
Sequence Annotations Expand
Reference Sequence

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(by identity cutoff) | 3D Structure

Entity ID: 2
Molecule	Chains	Sequence Length	Organism	Details	Image
Thrombin heavy chain	B [auth H]	259	Homo sapiens	Mutation(s): 0 EC: 3.4.21.5
UniProt & NIH Common Fund Data Resources
Find proteins for P00734 (Homo sapiens) Explore P00734 Go to UniProtKB: P00734
PHAROS: P00734 GTEx: ENSG00000180210
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt Group	P00734
Sequence Annotations Expand
Reference Sequence

Find similar proteins by: Sequence | 3D Structure

Entity ID: 3
Molecule	Chains	Sequence Length	Organism	Details	Image
synthetic peptide	C [auth P]	11	N/A	Mutation(s): 0
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
Sequence Annotations Expand
Reference Sequence

Small Molecules

Ligands 1 Unique
ID	Chains	Name / Formula / InChI Key	2D Diagram	3D Interactions
NA9 Query on NA9 Download Ideal Coordinates CCD File SDF format, chain D [auth H] MOL2 format, chain D [auth H]	D [auth H]	N-(CARBOXYMETHYL)-3-CYCLOHEXYL-D-ALANYL-N-({6-[AMINO(IMINO)METHYL]PYRIDIN-3-YL}METHYL)-N~2~-METHYL-L-ALANINAMIDE C₂₂ H₃₄ N₆ O₄ XVBUQSSETBYPJB-KBXCAEBGSA-N		Interactions Focus chain D [auth H] Interactions & Density Focus chain D [auth H]

Modified Residues 3 Unique
ID	Chains	Type	Formula	2D Diagram	Parent
ALC Query on ALC	C [auth P]	L-PEPTIDE LINKING	C₉ H₁₇ N O₂		ALA
HYP Query on HYP	C [auth P]	L-PEPTIDE LINKING	C₅ H₉ N O₃		PRO
SMF Query on SMF	C [auth P]	L-PEPTIDE LINKING	C₁₀ H₁₃ N O₅ S		PHE

Binding Affinity Annotations
ID	Source	Binding Affinity
NA9	Binding MOAD: 2A2X	IC50: 20.2 (nM) from 1 assay(s)
	PDBBind: 2A2X	IC50: 20.2 (nM) from 1 assay(s)
	BindingDB: 2A2X	IC50: 20.2 (nM) from 1 assay(s)

Biologically Interesting Molecules (External Reference) 1 Unique

Entity ID: 3
ID	Chains	Name	Type/Class	2D Diagram	3D Interactions
PRD_000480 Query on PRD_000480	C [auth P]	HIRUDIN ANALOGUE	Oligopeptide / Anticoagulant, Antithrombotic		Interactions Focus chain C [auth P] Interactions & Density Focus chain C [auth P]

Experimental Data & Validation

Experimental Data

Method: X-RAY DIFFRACTION
Resolution: 2.44 Å
R-Value Free: 0.221
R-Value Work: 0.198
Space Group: C 1 2 1

Unit Cell:

Length ( Å )	Angle ( ˚ )
a = 71.24	α = 90
b = 72.39	β = 101.01
c = 73.06	γ = 90

Software Package:

Software Name	Purpose
CNS	refinement
PDB_EXTRACT	data extraction
FRAMBO	data collection
SAINT	data scaling
CNS	phasing

Structure Validation

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Ligand Structure Quality Assessment

Entry History

Deposition Data

Released Date: 2006-11-14

Deposition Author(s):

Revision History (Full details and data files)

Version 1.0: 2006-11-14
Type: Initial release
Version 1.1: 2008-04-30
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: 2017-10-11
Changes: Refinement description
Version 1.5: 2018-04-04
Changes: Data collection
Version 1.6: 2023-08-23
Changes: Data collection, Database references, Derived calculations, Refinement description, Structure summary