[English] 日本語
Yorodumi
- PDB-7lmx: A HIGHLY SPECIFIC INHIBITOR OF INTEGRIN ALPHA-V BETA-6 WITH A DIS... -

+
Open data


ID or keywords:

Loading...

-
Basic information

Entry
Database: PDB / ID: 7lmx
TitleA HIGHLY SPECIFIC INHIBITOR OF INTEGRIN ALPHA-V BETA-6 WITH A DISULFIDE
ComponentsIntegrin inhibitor
KeywordsDE NOVO PROTEIN / de novo design / inhibitor / integrin / fibrosis
Biological speciessynthetic construct (others)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.8 Å
AuthorsDong, X. / Bera, A.K. / Roy, A. / Shi, L. / Springer, T.A. / Baker, D.
Funding support United States, 1items
OrganizationGrant numberCountry
Howard Hughes Medical Institute (HHMI) United States
CitationJournal: Nat Commun / Year: 2023
Title: De novo design of highly selective miniprotein inhibitors of integrins αvβ6 and αvβ8.
Authors: Anindya Roy / Lei Shi / Ashley Chang / Xianchi Dong / Andres Fernandez / John C Kraft / Jing Li / Viet Q Le / Rebecca Viazzo Winegar / Gerald Maxwell Cherf / Dean Slocum / P Daniel Poulson / ...Authors: Anindya Roy / Lei Shi / Ashley Chang / Xianchi Dong / Andres Fernandez / John C Kraft / Jing Li / Viet Q Le / Rebecca Viazzo Winegar / Gerald Maxwell Cherf / Dean Slocum / P Daniel Poulson / Garrett E Casper / Mary L Vallecillo-Zúniga / Jonard Corpuz Valdoz / Marcos C Miranda / Hua Bai / Yakov Kipnis / Audrey Olshefsky / Tanu Priya / Lauren Carter / Rashmi Ravichandran / Cameron M Chow / Max R Johnson / Suna Cheng / McKaela Smith / Catherine Overed-Sayer / Donna K Finch / David Lowe / Asim K Bera / Gustavo Matute-Bello / Timothy P Birkland / Frank DiMaio / Ganesh Raghu / Jennifer R Cochran / Lance J Stewart / Melody G Campbell / Pam M Van Ry / Timothy Springer / David Baker /
Abstract: The RGD (Arg-Gly-Asp)-binding integrins αvβ6 and αvβ8 are clinically validated cancer and fibrosis targets of considerable therapeutic importance. Compounds that can discriminate between ...The RGD (Arg-Gly-Asp)-binding integrins αvβ6 and αvβ8 are clinically validated cancer and fibrosis targets of considerable therapeutic importance. Compounds that can discriminate between homologous αvβ6 and αvβ8 and other RGD integrins, stabilize specific conformational states, and have high thermal stability could have considerable therapeutic utility. Existing small molecule and antibody inhibitors do not have all these properties, and hence new approaches are needed. Here we describe a generalized method for computationally designing RGD-containing miniproteins selective for a single RGD integrin heterodimer and conformational state. We design hyperstable, selective αvβ6 and αvβ8 inhibitors that bind with picomolar affinity. CryoEM structures of the designed inhibitor-integrin complexes are very close to the computational design models, and show that the inhibitors stabilize specific conformational states of the αvβ6 and the αvβ8 integrins. In a lung fibrosis mouse model, the αvβ6 inhibitor potently reduced fibrotic burden and improved overall lung mechanics, demonstrating the therapeutic potential of de novo designed integrin binding proteins with high selectivity.
History
DepositionFeb 6, 2021Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 10, 2022Provider: repository / Type: Initial release
Revision 1.1Feb 21, 2024Group: Data collection / Database references
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2Apr 3, 2024Group: Refinement description / Category: pdbx_initial_refinement_model
Revision 1.3Oct 30, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature

-
Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

-
Assembly

Deposited unit
A: Integrin inhibitor
B: Integrin inhibitor
C: Integrin inhibitor


Theoretical massNumber of molelcules
Total (without water)25,6413
Polymers25,6413
Non-polymers00
Water1,65792
1
A: Integrin inhibitor


Theoretical massNumber of molelcules
Total (without water)8,5471
Polymers8,5471
Non-polymers00
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Integrin inhibitor


Theoretical massNumber of molelcules
Total (without water)8,5471
Polymers8,5471
Non-polymers00
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3
C: Integrin inhibitor


Theoretical massNumber of molelcules
Total (without water)8,5471
Polymers8,5471
Non-polymers00
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)40.690, 64.100, 80.990
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121
Space group name HallP2ac2ab
Symmetry operation#1: x,y,z
#2: x+1/2,-y+1/2,-z
#3: -x,y+1/2,-z+1/2
#4: -x+1/2,-y,z+1/2

-
Components

#1: Protein Integrin inhibitor


Mass: 8546.846 Da / Num. of mol.: 3
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) synthetic construct (others) / Production host: Escherichia coli (E. coli)
#2: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 92 / Source method: isolated from a natural source / Formula: H2O
Has protein modificationY

-
Experimental details

-
Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

-
Sample preparation

CrystalDensity Matthews: 2.06 Å3/Da / Density % sol: 40.28 %
Crystal growTemperature: 297 K / Method: vapor diffusion, hanging drop / Details: 0.2 M tripotassium citrate, 20% PEG3350

-
Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 23-ID-B / Wavelength: 1.07212 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Oct 18, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.07212 Å / Relative weight: 1
ReflectionResolution: 1.8→40.69 Å / Num. obs: 20120 / % possible obs: 98.9 % / Redundancy: 6 % / Biso Wilson estimate: 26.21 Å2 / CC1/2: 0.995 / Rmerge(I) obs: 0.087 / Net I/σ(I): 13.5
Reflection shellResolution: 1.8→1.86 Å / Mean I/σ(I) obs: 2.5 / Num. unique obs: 20060 / CC1/2: 0.739

-
Processing

Software
NameVersionClassification
PHENIX1.18rc2_3793refinement
XDSdata reduction
XDSdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: Design Model

Resolution: 1.8→25.18 Å / SU ML: 0.282 / Cross valid method: FREE R-VALUE / σ(F): 1.37 / Phase error: 30.7408
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2618 1005 5.01 %
Rwork0.2283 19065 -
obs0.23 20070 98.95 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 44.45 Å2
Refinement stepCycle: LAST / Resolution: 1.8→25.18 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1777 0 0 92 1869
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00371813
X-RAY DIFFRACTIONf_angle_d0.60572442
X-RAY DIFFRACTIONf_chiral_restr0.0475273
X-RAY DIFFRACTIONf_plane_restr0.003308
X-RAY DIFFRACTIONf_dihedral_angle_d11.9775671
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.8-1.890.37911420.32542698X-RAY DIFFRACTION99.89
1.89-2.010.33121430.25952699X-RAY DIFFRACTION99.82
2.01-2.170.31361420.23882716X-RAY DIFFRACTION99.72
2.17-2.390.26491430.24092709X-RAY DIFFRACTION99.2
2.39-2.730.27431410.23652696X-RAY DIFFRACTION98.68
2.73-3.440.25321450.22832741X-RAY DIFFRACTION98.73
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
14.946717180611.042728596151.241605077837.618135451741.800136737294.60462954630.283096798284-0.251663089429-0.1405660150280.996188156333-0.153842879153-0.1613461415850.1004127804050.235228117235-0.1526081037150.265481753098-0.101041103461-0.01569844877940.2769358487440.02297955333770.168361618352-5.66666389997-1.87521560214-20.4732355145
23.900763433410.09334534622751.052489762279.08217763168-0.8198944460657.105254485770.4235768083390.05825010582760.1281332751810.456389650739-0.259499944356-0.4831556496650.08604355310150.787763915412-0.1773062798170.243674161055-0.09596698400720.01205046376940.334180347126-0.009060931907120.266457272791-3.567176297624.33394989415-22.4041992363
32.53021675071-1.762869549580.2825881600443.576134013922.395811596622.912073951420.52566337786-0.6475595892330.3565774561061.65509405538-0.1135022137030.725252895988-0.213399734319-0.196126223054-0.1485363137690.609754350528-0.1143839197270.2698570108880.373349405594-0.08308323559420.421230202325-14.10474409070.773395042705-14.9170309478
42.46732754678-0.2007598925021.027687960785.402409819462.937969423382.088672832380.195312838273-0.9818839752560.8998019287821.438202517270.178487470307-0.533238068924-0.5813902185040.464741995014-0.03028083938151.33161424988-0.258406058830.08125740164310.448534276643-0.2259723540860.184354688016-5.603385274112.31818181143-11.770796325
53.19135871289-1.910723553270.4375648471394.10116109722.894691271913.5312453660.7641414268930.2106147584170.7630474551110.1603961758630.143378470258-0.05480594975920.4378589909460.230786864387-0.5425799153490.4851814996620.05909023593550.01260533996980.309080616378-0.05975627104340.379130977887-19.48095288572.20106752036-36.1120850401
67.432310258061.50328826773-4.01289130547.58429820195-1.643932015216.66231334821-0.04622423410.6104689964850.297458341255-0.974972065018-0.1953382572250.23121782284-0.316880190434-1.39490968610.04748734641640.3887651073820.0755780521858-0.08542026252040.335268065377-0.07717940342450.340644060863-29.188499312212.3486278584-31.0036508176
74.575639652740.150470442027-0.5940764870565.15166218469-0.6461192147168.10498806211-0.3028123210030.6839045465320.0169778445004-1.44825321711-0.03076834393250.381600239262-0.233558799175-0.2354591094460.1185897120020.5813089719650.103340383337-0.1101776811210.480135159434-0.08361856559240.28655339249-25.73559434165.22831866202-39.1096373035
87.64767834109-1.29983698502-1.0434534119.356249344364.572261627832.930710015880.2253340677160.3016581941910.0633931563614-0.642152935659-0.3300735265380.0543022249261-0.0384559362093-0.1088000265250.06520567295160.3145064875130.001242752678780.04982993021490.295567736188-0.0004510218309390.237473265065-17.39831326589.11843586439-30.8239654761
93.99161621746-0.878191600661-3.641576055867.035161570170.9333768825653.4130122376-0.2869213079710.4362389972730.0504430772341-0.7626920340940.788914092851-0.04302480623890.344748811365-0.367740118008-0.3016700155080.269941871052-0.07800166989340.01472465141550.357768700491-0.01005243969140.284450973147-17.6207114355-20.8041238485-39.3068206639
105.55663632481-0.709825941232-2.154007372071.82057617651-0.234707088497.29409532795-0.0303638799667-0.170242346003-0.6481326059880.079039160452-0.2829410335650.07548400625980.1445343990840.5408844165680.2658005438940.1463461167220.0168080937854-0.008936695443770.2135150865140.02104702017790.27778489613-9.65777872235-14.8638481558-28.2970719742
116.55650500944-0.532963223619-1.227441260472.50784600222-1.616302322847.37586548283-0.146016177490.236562379236-0.1292004455250.001984453619190.1097849205380.1926208914810.389730990472-0.01838340762520.007589522119120.216087910091-0.009944376413250.05536252671370.248707534754-0.005235734625690.329101625605-12.6032129772-19.8627563876-36.7121544284
128.284214061930.8580977701380.5810213797735.087714282370.9612852333195.63188851548-0.238151285335-0.305489122215-0.141357899067-0.241619605460.1422877946880.3256672153870.0319081154716-0.9473844734990.1261161311180.302376601431-0.03257129625020.06155264729470.299216916980.07148335250430.30067953222-18.4338552192-23.1041982425-33.4352393444
Refinement TLS group

Refine-ID: X-RAY DIFFRACTION

IDRefine TLS-IDSelection detailsAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
11chain 'A' and (resid 0 through 28 )AA0 - 281 - 29
22chain 'A' and (resid 29 through 49 )AA29 - 4930 - 50
33chain 'A' and (resid 50 through 63 )AA50 - 6351 - 64
44chain 'A' and (resid 64 through 74 )AA64 - 7465 - 75
55chain 'B' and (resid 1 through 8 )BB1 - 81 - 8
66chain 'B' and (resid 9 through 28 )BB9 - 289 - 28
77chain 'B' and (resid 29 through 49 )BB29 - 4929 - 49
88chain 'B' and (resid 50 through 73 )BB50 - 7350 - 73
99chain 'C' and (resid 1 through 8 )CC1 - 81 - 8
1010chain 'C' and (resid 9 through 28 )CC9 - 289 - 28
1111chain 'C' and (resid 29 through 63 )CC29 - 6329 - 63
1212chain 'C' and (resid 64 through 74 )CC64 - 7464 - 74

+
About Yorodumi

-
News

-
Feb 9, 2022. New format data for meta-information of EMDB entries

New format data for meta-information of EMDB entries

  • Version 3 of the EMDB header file is now the official format.
  • The previous official version 1.9 will be removed from the archive.

Related info.:EMDB header

External links:wwPDB to switch to version 3 of the EMDB data model

-
Aug 12, 2020. Covid-19 info

Covid-19 info

URL: https://pdbj.org/emnavi/covid19.php

New page: Covid-19 featured information page in EM Navigator.

Related info.:Covid-19 info / Mar 5, 2020. Novel coronavirus structure data

+
Mar 5, 2020. Novel coronavirus structure data

Novel coronavirus structure data

Related info.:Yorodumi Speices / Aug 12, 2020. Covid-19 info

External links:COVID-19 featured content - PDBj / Molecule of the Month (242)：Coronavirus Proteases

+
Jan 31, 2019. EMDB accession codes are about to change! (news from PDBe EMDB page)

EMDB accession codes are about to change! (news from PDBe EMDB page)

  • The allocation of 4 digits for EMDB accession codes will soon come to an end. Whilst these codes will remain in use, new EMDB accession codes will include an additional digit and will expand incrementally as the available range of codes is exhausted. The current 4-digit format prefixed with “EMD-” (i.e. EMD-XXXX) will advance to a 5-digit format (i.e. EMD-XXXXX), and so on. It is currently estimated that the 4-digit codes will be depleted around Spring 2019, at which point the 5-digit format will come into force.
  • The EM Navigator/Yorodumi systems omit the EMD- prefix.

Related info.:Q: What is EMD? / ID/Accession-code notation in Yorodumi/EM Navigator

External links:EMDB Accession Codes are Changing Soon! / Contact to PDBj

+
Jul 12, 2017. Major update of PDB

Major update of PDB

  • wwPDB released updated PDB data conforming to the new PDBx/mmCIF dictionary.
  • This is a major update changing the version number from 4 to 5, and with Remediation, in which all the entries are updated.
  • In this update, many items about electron microscopy experimental information are reorganized (e.g. em_software).
  • Now, EM Navigator and Yorodumi are based on the updated data.

External links:wwPDB Remediation / Enriched Model Files Conforming to OneDep Data Standards Now Available in the PDB FTP Archive

-
Yorodumi

Thousand views of thousand structures

  • Yorodumi is a browser for structure data from EMDB, PDB, SASBDB, etc.
  • This page is also the successor to EM Navigator detail page, and also detail information page/front-end page for Omokage search.
  • The word "yorodu" (or yorozu) is an old Japanese word meaning "ten thousand". "mi" (miru) is to see.

Related info.:EMDB / PDB / SASBDB / Comparison of 3 databanks / Yorodumi Search / Aug 31, 2016. New EM Navigator & Yorodumi / Yorodumi Papers / Jmol/JSmol / Function and homology information / Changes in new EM Navigator and Yorodumi

Read more