4B9K

pVHL-ELOB-ELOC complex_(2S,4R)-1-(3-amino-2-methylbenzoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide bound

PDB DOI: https://doi.org/10.2210/pdb4B9K/pdb

Classification: LIGASE
Organism(s): Homo sapiens
Expression System: Escherichia coli BL21(DE3)
Mutation(s): No

Deposited: 2012-09-05 Released: 2012-10-24
Deposition Author(s): Buckley, D.L., Gustafson, J.L., VanMolle, I., Roth, A.G., SeopTae, H., Gareiss, P.C., Jorgensen, W.L., Ciulli, A., Crews, C.M.

Experimental Data Snapshot

Method: X-RAY DIFFRACTION
Resolution: 2.00 Å
R-Value Free: 0.220
R-Value Work: 0.189
R-Value Observed: 0.190

wwPDB Validation 3D Report Full Report

Ligand Structure Quality Assessment

This is version 1.2 of the entry. See complete history.

Literature

Small-Molecule Inhibitors of the Interaction between the E3 Ligase Vhl and Hif1 Alpha

Buckley, D.L., Gustafson, J.L., Van Molle, I., Roth, A.G., Tae, H.S., Gareiss, P.C., Jorgensen, W.L., Ciulli, A., Crews, C.M.

(2012) Angew Chem Int Ed Engl 51: 11463

PubMed: 23065727 Search on PubMedSearch on PubMed Central
DOI: https://doi.org/10.1002/anie.201206231
Primary Citation of Related Structures:
4B95, 4B9K

PubMed Abstract:
E3 ubiquitin ligases, such as the therapeutically relevant VHL, are challenging targets for traditional medicinal chemistry, as their modulation requires targeting protein-protein interactions. We report novel small-molecule inhibitors of the interaction between VHL and its molecular target HIF1α, a transcription factor involved in oxygen sensing.

Organizational Affiliation

Department of Chemistry, Yale University, New Haven, CT 06511, USA.

Macromolecule Content

Total Structure Weight: 173.73 kDa
Atom Count: 11,711
Modelled Residue Count: 1,339
Deposited Residue Count: 1,488
Unique protein chains: 4

Macromolecules

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(by identity cutoff) | 3D Structure

Entity ID: 1
Molecule	Chains	Sequence Length	Organism	Details	Image
TRANSCRIPTION ELONGATION FACTOR B POLYPEPTIDE 2	A, D, G, J	104	Homo sapiens	Mutation(s): 0
UniProt & NIH Common Fund Data Resources
Find proteins for Q15370 (Homo sapiens) Explore Q15370 Go to UniProtKB: Q15370
PHAROS: Q15370 GTEx: ENSG00000103363
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt Group	Q15370
Sequence Annotations Expand
Reference Sequence

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(by identity cutoff) | 3D Structure

Entity ID: 2
Molecule	Chains	Sequence Length	Organism	Details	Image
TRANSCRIPTION ELONGATION FACTOR B POLYPEPTIDE 1	B, H, K	97	Homo sapiens	Mutation(s): 0
UniProt & NIH Common Fund Data Resources
Find proteins for Q15369 (Homo sapiens) Explore Q15369 Go to UniProtKB: Q15369
PHAROS: Q15369 GTEx: ENSG00000154582
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt Group	Q15369
Sequence Annotations Expand
Reference Sequence

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(by identity cutoff) | 3D Structure

Entity ID: 3
Molecule	Chains	Sequence Length	Organism	Details	Image
VON HIPPEL-LINDAU DISEASE TUMOR SUPPRESSOR	C, F, I, L	171	Homo sapiens	Mutation(s): 0
UniProt & NIH Common Fund Data Resources
Find proteins for P40337 (Homo sapiens) Explore P40337 Go to UniProtKB: P40337
PHAROS: P40337 GTEx: ENSG00000134086
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt Group	P40337
Sequence Annotations Expand
Reference Sequence

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(by identity cutoff) | 3D Structure

Entity ID: 4
Molecule	Chains	Sequence Length	Organism	Details	Image
TRANSCRIPTION ELONGATION FACTOR B POLYPEPTIDE 1	E	97	Homo sapiens	Mutation(s): 0
UniProt & NIH Common Fund Data Resources
Find proteins for Q15369 (Homo sapiens) Explore Q15369 Go to UniProtKB: Q15369
PHAROS: Q15369 GTEx: ENSG00000154582
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt Group	Q15369
Sequence Annotations Expand
Reference Sequence

Small Molecules

Ligands 2 Unique
ID	Chains	Name / Formula / InChI Key	2D Diagram	3D Interactions
TG0 Query on TG0 Download Ideal Coordinates CCD File SDF format, chain M [auth C] SDF format, chain O [auth F] SDF format, chain T [auth I] SDF format, chain W [auth L] MOL2 format, chain M [auth C] MOL2 format, chain O [auth F] MOL2 format, chain T [auth I] MOL2 format, chain W [auth L]	M [auth C], O [auth F], T [auth I], W [auth L]	(2S,4R)-1-(3-amino-2-methylbenzoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide C₂₄ H₂₆ N₄ O₃ S AFUSGLDYQSDIEU-NQIIRXRSSA-N		Interactions Focus chain M [auth C] Focus chain O [auth F] Focus chain T [auth I] Focus chain W [auth L] Interactions & Density Focus chain M [auth C] Focus chain O [auth F] Focus chain T [auth I] Focus chain W [auth L]
ACT Query on ACT Download Ideal Coordinates CCD File SDF format, chain N [auth F] SDF format, chain S [auth I] SDF format, chain V [auth L] SDF format, chain X [auth L] SDF format, chain P [auth F] SDF format, chain Q [auth H] SDF format, chain R [auth H] SDF format, chain U [auth K] MOL2 format, chain N [auth F] MOL2 format, chain S [auth I] MOL2 format, chain V [auth L] MOL2 format, chain X [auth L] MOL2 format, chain P [auth F] MOL2 format, chain Q [auth H] MOL2 format, chain R [auth H] MOL2 format, chain U [auth K]	N [auth F] P [auth F] Q [auth H] R [auth H] S [auth I] N [auth F], P [auth F], Q [auth H], R [auth H], S [auth I], U [auth K], V [auth L], X [auth L]	ACETATE ION C₂ H₃ O₂ QTBSBXVTEAMEQO-UHFFFAOYSA-M		Interactions Focus chain N [auth F] Focus chain P [auth F] Focus chain Q [auth H] Focus chain R [auth H] Focus chain S [auth I] Focus chain U [auth K] Focus chain V [auth L] Focus chain X [auth L] Interactions & Density Focus chain N [auth F] Focus chain P [auth F] Focus chain Q [auth H] Focus chain R [auth H] Focus chain S [auth I] Focus chain U [auth K] Focus chain V [auth L] Focus chain X [auth L]

Modified Residues 1 Unique
ID	Chains	Type	Formula	2D Diagram	Parent
CAS Query on CAS	A, D, G, J	L-PEPTIDE LINKING	C₅ H₁₂ As N O₂ S		CYS

Binding Affinity Annotations
ID	Source	Binding Affinity
TG0	PDBBind: 4B9K	Ki: 670 (nM) from 1 assay(s)
	Binding MOAD: 4B9K	Ki: 670 (nM) from 1 assay(s)
	BindingDB: 4B9K	IC50: min: 670, max: 900 (nM) from 2 assay(s)