3PO6

Crystal structure of human carbonic anhydrase II with 6,7-Dimethoxy-1-methyl-3,4-dihydroisoquinoline-2(1H)-sulfonamide

PDB DOI: https://doi.org/10.2210/pdb3PO6/pdb

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

Deposited: 2010-11-22 Released: 2011-04-06
Deposition Author(s): Mader, P., Brynda, J., Gitto, R., Agnello, S., Ferro, S., De Luca, L., Vullo, D., Supuran, C.T., Chimirri, A.

Experimental Data Snapshot

Method: X-RAY DIFFRACTION
Resolution: 1.47 Å
R-Value Free: 0.175
R-Value Work: 0.143
R-Value Observed: 0.145

wwPDB Validation 3D Report Full Report

Ligand Structure Quality Assessment

This is version 1.3 of the entry. See complete history.

Literature

Structural basis for the interaction between carbonic anhydrase and 1,2,3,4-tetrahydroisoquinolin-2-ylsulfonamides.

Mader, P., Brynda, J., Gitto, R., Agnello, S., Pachl, P., Supuran, C.T., Chimirri, A., Rezacova, P.

(2011) J Med Chem 54: 2522-2526

PubMed: 21395315 Search on PubMed
DOI: https://doi.org/10.1021/jm2000213
Primary Citation of Related Structures:
3PO6

PubMed Abstract:
Isoquinolinesulfonamides inhibit human carbonic anhydrases (hCAs) and display selectivity toward therapeutically relevant isozymes. The crystal structure of hCA II in complex with 6,7-dimethoxy-1-methyl-1,2,3,4-tetrahydroisoquinolin-2-ylsulfonamide revealed unusual inhibitor binding. Structural analyses allowed for discerning the fine details of the inhibitor binding mode to the active site, thus providing clues for the future design of even more selective inhibitors for druggable isoforms such as the cancer associated hCA IX and neuronal hCA VII.

Organizational Affiliation

Department of Structural Biology, Institute of Molecular Genetics, Academy of Sciences of the Czech Republic, Prague, Czech Republic.

Macromolecule Content

Total Structure Weight: 30.22 kDa
Atom Count: 2,510
Modelled Residue Count: 258
Deposited Residue Count: 259
Unique protein chains: 1

Macromolecules

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(by identity cutoff) | 3D Structure

Entity ID: 1
Molecule	Chains	Sequence Length	Organism	Details	Image
Carbonic anhydrase 2	A	259	Homo sapiens	Mutation(s): 0 EC: 4.2.1.1 (PDB Primary Data), 4.2.1.69 (UniProt)
UniProt & NIH Common Fund Data Resources
Find proteins for P00918 (Homo sapiens) Explore P00918 Go to UniProtKB: P00918
PHAROS: P00918 GTEx: ENSG00000104267
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt Group	P00918
Sequence Annotations Expand
Reference Sequence

Small Molecules

Ligands 5 Unique
ID	Chains	Name / Formula / InChI Key	2D Diagram	3D Interactions
RDT Query on RDT Download Ideal Coordinates CCD File SDF format, chain D [auth A] MOL2 format, chain D [auth A] mmCIF format, chain D [auth A]	D [auth A]	(1R)-6,7-dimethoxy-1-methyl-3,4-dihydroisoquinoline-2(1H)-sulfonamide C₁₂ H₁₈ N₂ O₄ S GUJQIHRSATWPQA-MRVPVSSYSA-N		Interactions Focus chain D [auth A] Interactions & Density Focus chain D [auth A]
DT9 Query on DT9 Download Ideal Coordinates CCD File SDF format, chain C [auth A] MOL2 format, chain C [auth A] mmCIF format, chain C [auth A]	C [auth A]	(1S)-6,7-dimethoxy-1-methyl-3,4-dihydroisoquinoline-2(1H)-sulfonamide C₁₂ H₁₈ N₂ O₄ S GUJQIHRSATWPQA-QMMMGPOBSA-N		Interactions Focus chain C [auth A] Interactions & Density Focus chain C [auth A]
GOL Query on GOL Download Ideal Coordinates CCD File SDF format, chain E [auth A] SDF format, chain F [auth A] SDF format, chain G [auth A] SDF format, chain H [auth A] MOL2 format, chain E [auth A] MOL2 format, chain F [auth A] MOL2 format, chain G [auth A] MOL2 format, chain H [auth A] mmCIF format, chain E [auth A] mmCIF format, chain F [auth A] mmCIF format, chain G [auth A] mmCIF format, chain H [auth A]	E [auth A], F [auth A], G [auth A], H [auth A]	GLYCEROL C₃ H₈ O₃ PEDCQBHIVMGVHV-UHFFFAOYSA-N		Interactions Focus chain E [auth A] Focus chain F [auth A] Focus chain G [auth A] Focus chain H [auth A] Interactions & Density Focus chain E [auth A] Focus chain F [auth A] Focus chain G [auth A] Focus chain H [auth A]
ZN Query on ZN Download Ideal Coordinates CCD File SDF format, chain B [auth A] MOL2 format, chain B [auth A] mmCIF format, chain B [auth A]	B [auth A]	ZINC ION Zn PTFCDOFLOPIGGS-UHFFFAOYSA-N		Interactions Focus chain B [auth A] Interactions & Density Focus chain B [auth A]
ACT Query on ACT Download Ideal Coordinates CCD File SDF format, chain I [auth A] MOL2 format, chain I [auth A] mmCIF format, chain I [auth A]	I [auth A]	ACETATE ION C₂ H₃ O₂ QTBSBXVTEAMEQO-UHFFFAOYSA-M		Interactions Focus chain I [auth A] Interactions & Density Focus chain I [auth A]

Binding Affinity Annotations
ID	Source	Binding Affinity
DT9	PDBBind: 3PO6	Ki: 87.3 (nM) from 1 assay(s)

Experimental Data & Validation

Experimental Data

Method: X-RAY DIFFRACTION
Resolution: 1.47 Å
R-Value Free: 0.175
R-Value Work: 0.143
R-Value Observed: 0.145
Space Group: P 1 2₁ 1

Unit Cell:

Length ( Å )	Angle ( ˚ )
a = 42.18	α = 90
b = 41.21	β = 104.31
c = 72	γ = 90

Software Package:

Software Name	Purpose
REFMAC	refinement
MOSFLM	data reduction
SCALA	data scaling

Structure Validation

View Full Validation Report

Ligand Structure Quality Assessment

Entry History

Deposition Data

Released Date: 2011-04-06

Deposition Author(s):

Revision History (Full details and data files)

Version 1.0: 2011-04-06
Type: Initial release
Version 1.1: 2011-07-13
Changes: Version format compliance
Version 1.2: 2011-12-07
Changes: Database references
Version 1.3: 2024-03-20
Changes: Data collection, Database references, Derived calculations