4LZ4

X-ray structure of the complex between human thrombin and the TBA deletion mutant lacking thymine 3 nucleobase

PDB DOI: https://doi.org/10.2210/pdb4LZ4/pdb
NAKB: 4LZ4

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

Deposited: 2013-07-31 Released: 2014-01-08
Deposition Author(s): Pica, A., Russo Krauss, I., Merlino, A., Sica, F.

Experimental Data Snapshot

Method: X-RAY DIFFRACTION
Resolution: 2.56 ?
R-Value Free:
0.227 (Depositor), 0.228 (DCC)
R-Value Work:
0.168 (Depositor), 0.175 (DCC)
R-Value Observed:
0.171 (Depositor)

wwPDB Validation 3D Report Full Report

Ligand Structure Quality Assessment

This is version 2.1 of the entry. See complete history.

Literature

Dissecting the contribution of thrombin exosite I in the recognition of thrombin binding aptamer.

Pica, A., Russo Krauss, I., Merlino, A., Nagatoishi, S., Sugimoto, N., Sica, F.

(2013) FEBS J 280: 6581-6588

PubMed: 24128303 Search on PubMed
DOI: https://doi.org/10.1111/febs.12561
Primary Citation of Related Structures:
4LZ1, 4LZ4

PubMed Abstract:
Thrombin plays a pivotal role in the coagulation cascade; therefore, it represents a primary target in the treatment of several blood diseases. The 15-mer DNA oligonucleotide 5'-GGTTGGTGTGGTTGG-3', known as thrombin binding aptamer (TBA), is a highly potent inhibitor of the enzyme. TBA folds as an antiparallel chair-like G-quadruplex structure, with two G-tetrads surrounded by two TT loops on one side and a TGT loop on the opposite side. Previous crystallographic studies have shown that TBA binds thrombin exosite I by its TT loops, T3T4 and T12T13. In order to get a better understanding of the thrombin-TBA interaction, we have undertaken a crystallographic characterization of the complexes between thrombin and two TBA mutants, TBAΔT3 and TBAΔT12, which lack the nucleobase of T3 and T12, respectively. The structural details of the two complexes show that exosite I is actually split into two regions, which contribute differently to TBA recognition. These results provide the basis for a more rational design of new aptamers with improved therapeutic action.

Organizational Affiliation

Department of Chemical Sciences, University of Naples Federico II, Italy.

Macromolecule Content

Total Structure Weight: 78.47 kDa
Atom Count: 5,636
Modelled Residue Count: 614
Deposited Residue Count: 620
Unique protein chains: 2
Unique nucleic acid chains: 1

Macromolecules

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(by identity cutoff) | 3D Structure

Entity ID: 1
Molecule	Chains	Sequence Length	Organism	Details	Image
Thrombin light chain	A, C	36	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

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(by identity cutoff) | 3D Structure

Entity ID: 2
Molecule	Chains	Sequence Length	Organism	Details	Image
Thrombin heavy chain	B, D	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
Glycosylation
Glycosylation Sites: 1	Glycosylation Focus chain B Focus chain D	Go to GlyGen: P00734-1
Sequence Annotations Expand
Reference Sequence

Find similar nucleic acids by: Sequence | 3D Structure

Entity ID: 3
Molecule	Chains	Length	Organism	Image
Thrombin Binding Aptamer (TBA)	E, F	15	N/A
Sequence Annotations Expand
Reference Sequence

Small Molecules

Ligands 4 Unique
ID	Chains	Name / Formula / InChI Key	2D Diagram	3D Interactions
0G6 Query on 0G6 Download Ideal Coordinates CCD File SDF format, chain H [auth B] SDF format, chain K [auth D] MOL2 format, chain H [auth B] MOL2 format, chain K [auth D] mmCIF format, chain H [auth B] mmCIF format, chain K [auth D]	H [auth B], K [auth D]	D-phenylalanyl-N-[(2S,3S)-6-{[amino(iminio)methyl]amino}-1-chloro-2-hydroxyhexan-3-yl]-L-prolinamide C₂₁ H₃₄ Cl N₆ O₃ DVFLYEYCMMLBTQ-VSZNYVQBSA-O		Interactions Focus chain H [auth B] Focus chain K [auth D] Interactions & Density Focus chain H [auth B] Focus chain K [auth D]
NAG Query on NAG Download Ideal Coordinates CCD File SDF format, chain G [auth B] SDF format, chain J [auth D] MOL2 format, chain G [auth B] MOL2 format, chain J [auth D] mmCIF format, chain G [auth B] mmCIF format, chain J [auth D]	G [auth B], J [auth D]	2-acetamido-2-deoxy-beta-D-glucopyranose C₈ H₁₅ N O₆ OVRNDRQMDRJTHS-FMDGEEDCSA-N		Interactions Focus chain G [auth B] Focus chain J [auth D] Interactions & Density Focus chain G [auth B] Focus chain J [auth D]
K Query on K Download Ideal Coordinates CCD File SDF format, chain M [auth E] SDF format, chain N [auth F] MOL2 format, chain M [auth E] MOL2 format, chain N [auth F] mmCIF format, chain M [auth E] mmCIF format, chain N [auth F]	M [auth E], N [auth F]	POTASSIUM ION K NPYPAHLBTDXSSS-UHFFFAOYSA-N		Interactions Focus chain M [auth E] Focus chain N [auth F] Interactions & Density Focus chain M [auth E] Focus chain N [auth F]
NA Query on NA Download Ideal Coordinates CCD File SDF format, chain I [auth B] SDF format, chain L [auth D] MOL2 format, chain I [auth B] MOL2 format, chain L [auth D] mmCIF format, chain I [auth B] mmCIF format, chain L [auth D]	I [auth B], L [auth D]	SODIUM ION Na FKNQFGJONOIPTF-UHFFFAOYSA-N		Interactions Focus chain I [auth B] Focus chain L [auth D] Interactions & Density Focus chain I [auth B] Focus chain L [auth D]

Biologically Interesting Molecules (External Reference) 1 Unique

Entity ID: 5
ID	Chains	Name	Type/Class	2D Diagram	3D Interactions
PRD_000020 (0G6) Query on PRD_000020	H [auth B], K [auth D]	D-Phe-Pro-Arg-CH2Cl	Peptide-like / Inhibitor		Interactions Focus chain H [auth B] Focus chain K [auth D] Interactions & Density Focus chain H [auth B] Focus chain K [auth D]

Experimental Data & Validation

Experimental Data

Method: X-RAY DIFFRACTION
Resolution: 2.56 ?
R-Value Free: 0.227 (Depositor), 0.228 (DCC)
R-Value Work: 0.168 (Depositor), 0.175 (DCC)
R-Value Observed: 0.171 (Depositor)

Space Group: P 1 2₁ 1

Unit Cell:

Length ( ? )	Angle ( ? )
a = 61.736	α = 90
b = 120.725	β = 94.22
c = 67.233	γ = 90

Software Package:

Software Name	Purpose
CCP4	refinement
PHASER	phasing
REFMAC	refinement
HKL-2000	data reduction
HKL-2000	data scaling

Structure Validation

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Ligand Structure Quality Assessment

Entry History

Deposition Data

Released Date: 2014-01-08

Deposition Author(s):

Revision History (Full details and data files)

Version 1.0: 2014-01-08
Type: Initial release
Version 1.1: 2017-11-15
Changes: Refinement description
Version 2.0: 2020-07-29
Type: Remediation
Reason: Carbohydrate remediation
Changes: Atomic model, Data collection, Derived calculations, Structure summary
Version 2.1: 2024-10-30
Changes: Data collection, Database references, Structure summary