7ZXS

Crystal structure of DPP9 in complex with a 4-oxo-b-lactam based inhibitor, A295

PDB DOI: https://doi.org/10.2210/pdb7ZXS/pdb

Classification: HYDROLASE
Organism(s): Homo sapiens
Expression System: Spodoptera frugiperda
Mutation(s): No

Deposited: 2022-05-22 Released: 2022-09-28
Deposition Author(s): Ross, B., Huber, R.
Funding Organization(s): Max Planck Society

Experimental Data Snapshot

Method: X-RAY DIFFRACTION
Resolution: 1.81 Å
R-Value Free: 0.203
R-Value Work: 0.175
R-Value Observed: 0.175

Starting Model: experimental
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wwPDB Validation 3D Report Full Report

Ligand Structure Quality Assessment

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

Literature

Chemoproteomics-Enabled Identification of 4-Oxo-beta-Lactams as Inhibitors of Dipeptidyl Peptidases 8 and 9.

Carvalho, L.A.R., Ross, B., Fehr, L., Bolgi, O., Wohrle, S., Lum, K.M., Podlesainski, D., Vieira, A.C., Kiefersauer, R., Felix, R., Rodrigues, T., Lucas, S.D., Gross, O., Geiss-Friedlander, R., Cravatt, B.F., Huber, R., Kaiser, M., Moreira, R.

(2022) Angew Chem Int Ed Engl 61: e202210498-e202210498

PubMed: 36089535 Search on PubMedSearch on PubMed Central
DOI: https://doi.org/10.1002/anie.202210498
Primary Citation of Related Structures:
7A3G, 7A3J, 7A3L, 7AYQ, 7AYR, 7OR4, 7OZ7, 7ZXS

PubMed Abstract:
Dipeptidyl peptidases 8 and 9 (DPP8/9) have gathered interest as drug targets due to their important roles in biological processes like immunity and tumorigenesis. Elucidation of their distinct individual functions remains an ongoing task and could benefit from the availability of novel, chemically diverse and selective chemical tools. Here, we report the activity-based protein profiling (ABPP)-mediated discovery of 4-oxo-β-lactams as potent, non-substrate-like nanomolar DPP8/9 inhibitors. X-ray crystallographic structures revealed different ligand binding modes for DPP8 and DPP9, including an unprecedented targeting of an extended S2' (eS2') subsite in DPP8. Biological assays confirmed inhibition at both target and cellular levels. Altogether, our integrated chemical proteomics and structure-guided small molecule design approach led to novel DPP8/9 inhibitors with alternative molecular inhibition mechanisms, delivering the highest selectivity index reported to date.

Organizational Affiliation

Department of Pharmaceutical Sciences and Medicines, Research Institute for Medicines (iMed.ULisboa), Faculdade de Farmácia, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003, Lisboa, Portugal.

Macromolecule Content

Total Structure Weight: 394.3 kDa
Atom Count: 29,394
Modelled Residue Count: 3,364
Deposited Residue Count: 3,400
Unique protein chains: 2

Macromolecules

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(by identity cutoff) | 3D Structure

Entity ID: 1
Molecule	Chains	Sequence Length	Organism	Details	Image
Dipeptidyl peptidase 9	A, C	850	Homo sapiens	Mutation(s): 0 Gene Names: DPP9, DPRP2 EC: 3.4.14.5
UniProt & NIH Common Fund Data Resources
Find proteins for Q86TI2 (Homo sapiens) Explore Q86TI2 Go to UniProtKB: Q86TI2
PHAROS: Q86TI2 GTEx: ENSG00000142002
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt Group	Q86TI2
Sequence Annotations Expand
Reference Sequence

Find similar proteins by:

(by identity cutoff) | 3D Structure

Entity ID: 2
Molecule	Chains	Sequence Length	Organism	Details	Image
Dipeptidyl peptidase 9	B, D	850	Homo sapiens	Mutation(s): 0 Gene Names: DPP9, DPRP2 EC: 3.4.14.5
UniProt & NIH Common Fund Data Resources
Find proteins for Q86TI2 (Homo sapiens) Explore Q86TI2 Go to UniProtKB: Q86TI2
PHAROS: Q86TI2 GTEx: ENSG00000142002
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt Group	Q86TI2
Sequence Annotations Expand
Reference Sequence

Small Molecules

Ligands 3 Unique
ID	Chains	Name / Formula / InChI Key	2D Diagram	3D Interactions
KBO (Subject of Investigation/LOI) Query on KBO Download Ideal Coordinates CCD File SDF format, chain AA [auth C] SDF format, chain E [auth A] SDF format, chain M [auth B] SDF format, chain MA [auth D] MOL2 format, chain AA [auth C] MOL2 format, chain E [auth A] MOL2 format, chain M [auth B] MOL2 format, chain MA [auth D] mmCIF format, chain AA [auth C] mmCIF format, chain E [auth A] mmCIF format, chain M [auth B] mmCIF format, chain MA [auth D]	AA [auth C], E [auth A], M [auth B], MA [auth D]	2-ethyl-2-methanoyl-~{N}-[3-[[4-(quinolin-8-ylmethyl)piperazin-1-yl]methyl]phenyl]butanamide C₂₈ H₃₄ N₄ O₂ HUVCJXYEGHNBRX-UHFFFAOYSA-N		Interactions Focus chain AA [auth C] Focus chain E [auth A] Focus chain M [auth B] Focus chain MA [auth D] Interactions & Density Focus chain AA [auth C] Focus chain E [auth A] Focus chain M [auth B] Focus chain MA [auth D]
PEG Query on PEG Download Ideal Coordinates CCD File SDF format, chain IA [auth C] SDF format, chain XA [auth D] SDF format, chain Y [auth B] MOL2 format, chain IA [auth C] MOL2 format, chain XA [auth D] MOL2 format, chain Y [auth B] mmCIF format, chain IA [auth C] mmCIF format, chain XA [auth D] mmCIF format, chain Y [auth B]	IA [auth C], XA [auth D], Y [auth B]	DI(HYDROXYETHYL)ETHER C₄ H₁₀ O₃ MTHSVFCYNBDYFN-UHFFFAOYSA-N		Interactions Focus chain IA [auth C] Focus chain XA [auth D] Focus chain Y [auth B] Interactions & Density Focus chain IA [auth C] Focus chain XA [auth D] Focus chain Y [auth B]
EDO Query on EDO Download Ideal Coordinates CCD File SDF format, chain BA [auth C] SDF format, chain CA [auth C] SDF format, chain DA [auth C] SDF format, chain EA [auth C] SDF format, chain F [auth A] SDF format, chain FA [auth C] SDF format, chain G [auth A] SDF format, chain GA [auth C] SDF format, chain H [auth A] SDF format, chain HA [auth C] SDF format, chain I [auth A] SDF format, chain J [auth A] SDF format, chain JA [auth C] SDF format, chain K [auth A] SDF format, chain KA [auth C] SDF format, chain L [auth A] SDF format, chain LA [auth C] SDF format, chain N [auth B] SDF format, chain NA [auth D] SDF format, chain O [auth B] SDF format, chain OA [auth D] SDF format, chain P [auth B] SDF format, chain PA [auth D] SDF format, chain Q [auth B] SDF format, chain QA [auth D] SDF format, chain R [auth B] SDF format, chain RA [auth D] SDF format, chain S [auth B] SDF format, chain SA [auth D] SDF format, chain T [auth B] SDF format, chain TA [auth D] SDF format, chain U [auth B] SDF format, chain UA [auth D] SDF format, chain V [auth B] SDF format, chain VA [auth D] SDF format, chain W [auth B] SDF format, chain WA [auth D] SDF format, chain X [auth B] SDF format, chain YA [auth D] SDF format, chain Z [auth B] SDF format, chain ZA [auth D] MOL2 format, chain BA [auth C] MOL2 format, chain CA [auth C] MOL2 format, chain DA [auth C] MOL2 format, chain EA [auth C] MOL2 format, chain F [auth A] MOL2 format, chain FA [auth C] MOL2 format, chain G [auth A] MOL2 format, chain GA [auth C] MOL2 format, chain H [auth A] MOL2 format, chain HA [auth C] MOL2 format, chain I [auth A] MOL2 format, chain J [auth A] MOL2 format, chain JA [auth C] MOL2 format, chain K [auth A] MOL2 format, chain KA [auth C] MOL2 format, chain L [auth A] MOL2 format, chain LA [auth C] MOL2 format, chain N [auth B] MOL2 format, chain NA [auth D] MOL2 format, chain O [auth B] MOL2 format, chain OA [auth D] MOL2 format, chain P [auth B] MOL2 format, chain PA [auth D] MOL2 format, chain Q [auth B] MOL2 format, chain QA [auth D] MOL2 format, chain R [auth B] MOL2 format, chain RA [auth D] MOL2 format, chain S [auth B] MOL2 format, chain SA [auth D] MOL2 format, chain T [auth B] MOL2 format, chain TA [auth D] MOL2 format, chain U [auth B] MOL2 format, chain UA [auth D] MOL2 format, chain V [auth B] MOL2 format, chain VA [auth D] MOL2 format, chain W [auth B] MOL2 format, chain WA [auth D] MOL2 format, chain X [auth B] MOL2 format, chain YA [auth D] MOL2 format, chain Z [auth B] MOL2 format, chain ZA [auth D] mmCIF format, chain BA [auth C] mmCIF format, chain CA [auth C] mmCIF format, chain DA [auth C] mmCIF format, chain EA [auth C] mmCIF format, chain F [auth A] mmCIF format, chain FA [auth C] mmCIF format, chain G [auth A] mmCIF format, chain GA [auth C] mmCIF format, chain H [auth A] mmCIF format, chain HA [auth C] mmCIF format, chain I [auth A] mmCIF format, chain J [auth A] mmCIF format, chain JA [auth C] mmCIF format, chain K [auth A] mmCIF format, chain KA [auth C] mmCIF format, chain L [auth A] mmCIF format, chain LA [auth C] mmCIF format, chain N [auth B] mmCIF format, chain NA [auth D] mmCIF format, chain O [auth B] mmCIF format, chain OA [auth D] mmCIF format, chain P [auth B] mmCIF format, chain PA [auth D] mmCIF format, chain Q [auth B] mmCIF format, chain QA [auth D] mmCIF format, chain R [auth B] mmCIF format, chain RA [auth D] mmCIF format, chain S [auth B] mmCIF format, chain SA [auth D] mmCIF format, chain T [auth B] mmCIF format, chain TA [auth D] mmCIF format, chain U [auth B] mmCIF format, chain UA [auth D] mmCIF format, chain V [auth B] mmCIF format, chain VA [auth D] mmCIF format, chain W [auth B] mmCIF format, chain WA [auth D] mmCIF format, chain X [auth B] mmCIF format, chain YA [auth D] mmCIF format, chain Z [auth B] mmCIF format, chain ZA [auth D]	BA [auth C] CA [auth C] DA [auth C] EA [auth C] F [auth A] BA [auth C], CA [auth C], DA [auth C], EA [auth C], F [auth A], FA [auth C], G [auth A], GA [auth C], H [auth A], HA [auth C], I [auth A], J [auth A], JA [auth C], K [auth A], KA [auth C], L [auth A], LA [auth C], N [auth B], NA [auth D], O [auth B], OA [auth D], P [auth B], PA [auth D], Q [auth B], QA [auth D], R [auth B], RA [auth D], S [auth B], SA [auth D], T [auth B], TA [auth D], U [auth B], UA [auth D], V [auth B], VA [auth D], W [auth B], WA [auth D], X [auth B], YA [auth D], Z [auth B], ZA [auth D]	1,2-ETHANEDIOL C₂ H₆ O₂ LYCAIKOWRPUZTN-UHFFFAOYSA-N		Interactions Focus chain BA [auth C] Focus chain CA [auth C] Focus chain DA [auth C] Focus chain EA [auth C] Focus chain F [auth A] Focus chain FA [auth C] Focus chain G [auth A] Focus chain GA [auth C] Focus chain H [auth A] Focus chain HA [auth C] Focus chain I [auth A] Focus chain J [auth A] Focus chain JA [auth C] Focus chain K [auth A] Focus chain KA [auth C] Focus chain L [auth A] Focus chain LA [auth C] Focus chain N [auth B] Focus chain NA [auth D] Focus chain O [auth B] Focus chain OA [auth D] Focus chain P [auth B] Focus chain PA [auth D] Focus chain Q [auth B] Focus chain QA [auth D] Focus chain R [auth B] Focus chain RA [auth D] Focus chain S [auth B] Focus chain SA [auth D] Focus chain T [auth B] Focus chain TA [auth D] Focus chain U [auth B] Focus chain UA [auth D] Focus chain V [auth B] Focus chain VA [auth D] Focus chain W [auth B] Focus chain WA [auth D] Focus chain X [auth B] Focus chain YA [auth D] Focus chain Z [auth B] Focus chain ZA [auth D] Interactions & Density Focus chain BA [auth C] Focus chain CA [auth C] Focus chain DA [auth C] Focus chain EA [auth C] Focus chain F [auth A] Focus chain FA [auth C] Focus chain G [auth A] Focus chain GA [auth C] Focus chain H [auth A] Focus chain HA [auth C] Focus chain I [auth A] Focus chain J [auth A] Focus chain JA [auth C] Focus chain K [auth A] Focus chain KA [auth C] Focus chain L [auth A] Focus chain LA [auth C] Focus chain N [auth B] Focus chain NA [auth D] Focus chain O [auth B] Focus chain OA [auth D] Focus chain P [auth B] Focus chain PA [auth D] Focus chain Q [auth B] Focus chain QA [auth D] Focus chain R [auth B] Focus chain RA [auth D] Focus chain S [auth B] Focus chain SA [auth D] Focus chain T [auth B] Focus chain TA [auth D] Focus chain U [auth B] Focus chain UA [auth D] Focus chain V [auth B] Focus chain VA [auth D] Focus chain W [auth B] Focus chain WA [auth D] Focus chain X [auth B] Focus chain YA [auth D] Focus chain Z [auth B] Focus chain ZA [auth D]