3KHJ

C. parvum inosine monophosphate dehydrogenase bound by inhibitor C64

PDB DOI: https://doi.org/10.2210/pdb3KHJ/pdb

Classification: OXIDOREDUCTASE
Organism(s): Cryptosporidium parvum Iowa II
Expression System: Escherichia coli
Mutation(s): No

Deposited: 2009-10-30 Released: 2010-02-02
Deposition Author(s): MacPherson, I.S., Hedstrom, L.K.

Experimental Data Snapshot

Method: X-RAY DIFFRACTION
Resolution: 2.80 Å
R-Value Free: 0.266
R-Value Work: 0.224
R-Value Observed: 0.226

wwPDB Validation 3D Report Full Report

Ligand Structure Quality Assessment

This is version 1.4 of the entry. See complete history.

Literature

The structural basis of Cryptosporidium -specific IMP dehydrogenase inhibitor selectivity.

Macpherson, I.S., Kirubakaran, S., Gorla, S.K., Riera, T.V., D'Aquino, J.A., Zhang, M., Cuny, G.D., Hedstrom, L.

(2010) J Am Chem Soc 132: 1230-1231

PubMed: 20052976 Search on PubMedSearch on PubMed Central
DOI: https://doi.org/10.1021/ja909947a
Primary Citation of Related Structures:
3FFS, 3KHJ

PubMed Abstract:
Cryptosporidium parvum is a potential biowarfare agent, an important AIDS pathogen, and a major cause of diarrhea and malnutrition. No vaccines or effective drug treatment exist to combat Cryptosporidium infection. This parasite relies on inosine 5'-monophosphate dehydrogenase (IMPDH) to obtain guanine nucleotides, and inhibition of this enzyme blocks parasite proliferation. Here, we report the first crystal structures of CpIMPDH. These structures reveal the structural basis of inhibitor selectivity and suggest a strategy for further optimization. Using this information, we have synthesized low-nanomolar inhibitors that display 10(3) selectivity for the parasite enzyme over human IMPDH2.

Organizational Affiliation

Departments of Biology, Brandeis University, MS009, 415 South Street, Waltham, Massachusetts 02454, USA.

Macromolecule Content

Total Structure Weight: 312.22 kDa
Atom Count: 18,502
Modelled Residue Count: 2,473
Deposited Residue Count: 2,888
Unique protein chains: 1

Macromolecules

Find similar proteins by:

(by identity cutoff) | 3D Structure

Entity ID: 1
Molecule	Chains	Sequence Length	Organism	Details	Image
Inosine-5-monophosphate dehydrogenase	A, B, C, D, E A, B, C, D, E, F, G, H	361	Cryptosporidium parvum Iowa II	Mutation(s): 0 Gene Names: cgd6_20, GuaB EC: 1.1.1.205
UniProt
Find proteins for Q5CPK7 (Cryptosporidium parvum (strain Iowa II)) Explore Q5CPK7 Go to UniProtKB: Q5CPK7
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt Group	Q5CPK7
Sequence Annotations Expand
Reference Sequence

Small Molecules

Ligands 3 Unique
ID	Chains	Name / Formula / InChI Key	2D Diagram	3D Interactions
C64 Query on C64 Download Ideal Coordinates CCD File SDF format, chain K [auth B] SDF format, chain O [auth D] SDF format, chain T [auth H] MOL2 format, chain K [auth B] MOL2 format, chain O [auth D] MOL2 format, chain T [auth H] mmCIF format, chain K [auth B] mmCIF format, chain O [auth D] mmCIF format, chain T [auth H]	K [auth B], O [auth D], T [auth H]	N-(4-bromophenyl)-2-[2-(1,3-thiazol-2-yl)-1H-benzimidazol-1-yl]acetamide C₁₈ H₁₃ Br N₄ O S GUHIASUSWSGRHY-UHFFFAOYSA-N		Interactions Focus chain K [auth B] Focus chain O [auth D] Focus chain T [auth H] Interactions & Density Focus chain K [auth B] Focus chain O [auth D] Focus chain T [auth H]
IMP Query on IMP Download Ideal Coordinates CCD File SDF format, chain I [auth A] SDF format, chain J [auth B] SDF format, chain L [auth C] SDF format, chain M [auth D] SDF format, chain P [auth E] SDF format, chain Q [auth F] SDF format, chain R [auth G] SDF format, chain S [auth H] MOL2 format, chain I [auth A] MOL2 format, chain J [auth B] MOL2 format, chain L [auth C] MOL2 format, chain M [auth D] MOL2 format, chain P [auth E] MOL2 format, chain Q [auth F] MOL2 format, chain R [auth G] MOL2 format, chain S [auth H] mmCIF format, chain I [auth A] mmCIF format, chain J [auth B] mmCIF format, chain L [auth C] mmCIF format, chain M [auth D] mmCIF format, chain P [auth E] mmCIF format, chain Q [auth F] mmCIF format, chain R [auth G] mmCIF format, chain S [auth H]	I [auth A] J [auth B] L [auth C] M [auth D] P [auth E] I [auth A], J [auth B], L [auth C], M [auth D], P [auth E], Q [auth F], R [auth G], S [auth H]	INOSINIC ACID C₁₀ H₁₃ N₄ O₈ P GRSZFWQUAKGDAV-KQYNXXCUSA-N		Interactions Focus chain I [auth A] Focus chain J [auth B] Focus chain L [auth C] Focus chain M [auth D] Focus chain P [auth E] Focus chain Q [auth F] Focus chain R [auth G] Focus chain S [auth H] Interactions & Density Focus chain I [auth A] Focus chain J [auth B] Focus chain L [auth C] Focus chain M [auth D] Focus chain P [auth E] Focus chain Q [auth F] Focus chain R [auth G] Focus chain S [auth H]
ACT Query on ACT Download Ideal Coordinates CCD File SDF format, chain N [auth D] MOL2 format, chain N [auth D] mmCIF format, chain N [auth D]	N [auth D]	ACETATE ION C₂ H₃ O₂ QTBSBXVTEAMEQO-UHFFFAOYSA-M		Interactions Focus chain N [auth D] Interactions & Density Focus chain N [auth D]

Binding Affinity Annotations
ID	Source	Binding Affinity
C64	BindingDB: 3KHJ	IC50: min: 27, max: 28 (nM) from 2 assay(s)
C64	PDBBind: 3KHJ	IC50: 28 (nM) from 1 assay(s)

Experimental Data & Validation

Experimental Data

Method: X-RAY DIFFRACTION
Resolution: 2.80 Å
R-Value Free: 0.266
R-Value Work: 0.224
R-Value Observed: 0.226
Space Group: P 1 2₁ 1

Unit Cell:

Length ( Å )	Angle ( ˚ )
a = 83.481	α = 90
b = 166.141	β = 105.14
c = 101.289	γ = 90

Software Package:

Software Name	Purpose
ADSC	data collection
MOLREP	phasing
REFMAC	refinement
HKL-2000	data reduction
HKL-2000	data scaling

Structure Validation

View Full Validation Report

Ligand Structure Quality Assessment

Entry History

Deposition Data

Released Date: 2010-02-02

Deposition Author(s):

MacPherson, I.S.

Hedstrom, L.K.

Revision History (Full details and data files)

Version 1.0: 2010-02-02
Type: Initial release
Version 1.1: 2011-07-13
Changes: Version format compliance
Version 1.2: 2014-07-02
Changes: Structure summary
Version 1.3: 2017-08-02
Changes: Refinement description, Source and taxonomy
Version 1.4: 2024-02-21
Changes: Data collection, Database references, Derived calculations