7L05: Complex of novel maytansinoid M24

Complex of novel maytansinoid M24 bound to T2R-TTL (two tubulin alpha/beta heterodimers, RB3 stathmin-like domain, and tubulin tyrosine ligase). Determined by X-ray diffraction at 2.21 Å resolution. Released 22 Dec 2021.

Method: X-ray diffraction
Resolution: 2.21 Å
Organisms: Sus scrofa, Rattus norvegicus, Gallus gallus
Chains: 6
Atoms: 18,587
Mol. weight: 266.15 kDa
Ligands: CA, MG, GTP, ACP
Released: 22 Dec 2021

Explore 7L05 in 3D Show helices and sheets RCSB PDB PDBe

Secondary structure: helices and β-sheets

7L05 contains 121 α-helices and 90 β-strands across 6 chains. Residue ranges use author residue numbering, as in the PDB file, from PDBe. To see them in 3D, choose the Cartoon representation with Secondary structure coloring: helices, sheets and coils get different colors.

Chain A: 27 helices, 16 β-strands

Element	Residues	Length	Sheet
β-strand	4-9	6	1
α-helix	10-28	19
α-helix	48-51	4
β-strand	53-55	3	2
β-strand	61-63	3	2
β-strand	65-69	5	1
α-helix	73-80	8
α-helix	89-91	3
β-strand	92-94	3	1
α-helix	103-104	2
α-helix	105-110	6
α-helix	111-126	16
β-strand	134-140	7	1
α-helix	144	1
α-helix	145-149	5
α-helix	150-160	11
β-strand	165-172	8	1
α-helix	183-194	12
α-helix	195-197	3
β-strand	200-205	6	1
α-helix	206-216	11
α-helix	224-243	20
α-helix	252-259	8
α-helix	268	1
β-strand	269-273	5	3
β-strand	277	1	4
α-helix	284-287	4
α-helix	288-294	7
α-helix	298-300	3
β-strand	301	1	3
α-helix	307-309	3
β-strand	312-321	10	3
α-helix	325-338	14
β-strand	343	1	3
β-strand	349-356	8	3
α-helix	359-361	3
β-strand	368	1	4
α-helix	369-370	2
β-strand	373-381	9	3
α-helix	382-384	3
α-helix	385-399	15
α-helix	405-409	5
α-helix	416-436	21

Chain B: 24 helices, 20 β-strands

Element	Residues	Length	Sheet
β-strand	4-9	6	5
α-helix	10-27	18
β-strand	30	1	6
β-strand	35	1	7
β-strand	36	1	6
α-helix	41-43	3
α-helix	47-49	3
β-strand	51-54	4	7
β-strand	58-61	4	7
β-strand	63-67	5	5
α-helix	71-78	8
α-helix	82-84	3
α-helix	87-89	3
β-strand	90-92	3	5
α-helix	101-106	6
α-helix	108-125	18
β-strand	132-138	7	5
α-helix	143-147	5
α-helix	148-158	11
β-strand	163-170	8	5
β-strand	172	1	8
β-strand	175	1	8
α-helix	181-195	15
β-strand	198-203	6	5
α-helix	204-209	6
α-helix	210-214	5
α-helix	222-241	20
α-helix	250-257	8
β-strand	265-266	2	5
β-strand	267-271	5	9
α-helix	286-293	8
α-helix	296-298	3
β-strand	299	1	9
α-helix	305-307	3
β-strand	310-318	9	9
α-helix	323-336	14
α-helix	338-340	3
β-strand	341	1	9
β-strand	349-354	6	9
β-strand	372-379	8	9
α-helix	380-382	3
α-helix	383-397	15
α-helix	404-407	4
α-helix	413-435	23

Chain C: 30 helices, 14 β-strands

Element	Residues	Length	Sheet
β-strand	4-9	6	10
α-helix	10-28	19
α-helix	48-51	4
β-strand	53-55	3	11
β-strand	61-63	3	11
β-strand	65-69	5	10
α-helix	73-80	8
α-helix	89-91	3
β-strand	92-94	3	10
α-helix	103-104	2
α-helix	105-109	5
α-helix	111-113	3
α-helix	115-126	12
β-strand	134-140	7	10
α-helix	144	1
α-helix	145-149	5
α-helix	150-161	12
β-strand	165-172	8	10
α-helix	183-194	12
α-helix	195-197	3
β-strand	200-205	6	10
α-helix	206-216	11
α-helix	224-243	20
α-helix	252-259	8
α-helix	268	1
β-strand	269-273	5	12
α-helix	278-281	4
α-helix	288-294	7
α-helix	298-300	3
β-strand	301	1	12
α-helix	307-309	3
β-strand	312-321	10	12
α-helix	325-338	14
β-strand	343	1	12
α-helix	350-351	2
β-strand	352-356	5	12
α-helix	359-360	2
α-helix	369-370	2
β-strand	373-381	9	12
α-helix	382-384	3
α-helix	385-399	15
α-helix	405-409	5
α-helix	415-436	22
α-helix	438-439	2

Chain D: 24 helices, 18 β-strands

Element	Residues	Length	Sheet
β-strand	4-9	6	13
α-helix	10-27	18
β-strand	30	1	14
β-strand	35	1	15
β-strand	36	1	14
α-helix	41-43	3
α-helix	47-49	3
β-strand	51-54	4	15
β-strand	58-61	4	15
β-strand	63-67	5	13
α-helix	71-78	8
α-helix	82-84	3
α-helix	87-89	3
β-strand	90-92	3	13
α-helix	101-105	5
α-helix	108-125	18
β-strand	132-138	7	13
α-helix	143-147	5
α-helix	148-158	11
β-strand	163-170	8	13
α-helix	181-195	15
β-strand	198-203	6	13
α-helix	204-209	6
α-helix	210-214	5
α-helix	222-241	20
α-helix	250-257	8
β-strand	265-266	2	13
β-strand	267-271	5	16
α-helix	286-293	8
α-helix	296-298	3
β-strand	299	1	16
α-helix	305-307	3
β-strand	310-319	10	16
α-helix	323-336	14
α-helix	338-340	3
β-strand	341	1	16
β-strand	349-354	6	16
β-strand	371-379	9	16
α-helix	380-382	3
α-helix	383-397	15
α-helix	404-407	4
α-helix	413-435	23

Chain E: 1 helix, 2 β-strands

Element	Residues	Length	Sheet
β-strand	7-14	8	3
β-strand	17-25	9	3
α-helix	47-138	92

Chain F: 15 helices, 20 β-strands

Element	Residues	Length	Sheet
β-strand	2-6	5	17
α-helix	12-23	12
β-strand	27-29	3	17
α-helix	30-31	2
β-strand	39-41	3	17
α-helix	49-51	3
β-strand	61-62	2	17
α-helix	69-72	4
α-helix	74-83	10
β-strand	97-100	4	18
α-helix	128-141	14
β-strand	147-150	4	18
β-strand	161-163	3	18
α-helix	166-174	9
β-strand	180-184	5	18
β-strand	189	1	19
β-strand	192	1	20
β-strand	197	1	20
β-strand	199-207	9	21
β-strand	213-216	4	21
β-strand	220-223	4	21
α-helix	243-248	6
β-strand	261-262	2	21
α-helix	264-275	12
α-helix	279	1
α-helix	280-284	5
α-helix	285-302	18
β-strand	310-311	2	17
β-strand	313-321	9	21
β-strand	322	1	19
β-strand	327-333	7	21
α-helix	340-342	3
α-helix	343-350	8
α-helix	351-355	5
β-strand	375-378	4	21

Molecules and chains

Molecule	Chains	Type	Length	Organism	UniProt
Tubulin alpha-1B chain	A, C	protein	451	Sus scrofa	Q2XVP4 (AlphaFold model)
Tubulin beta chain	B, D	protein	445	Sus scrofa	P02554 (AlphaFold model)
Stathmin-4	E	protein	149	Rattus norvegicus	P63043 (AlphaFold model)
Tubulin Tyrosine Ligase	F	protein	384	Gallus gallus	A0A8V0Z8P0 (AlphaFold model)

Sequence of entity 1 (A, C), FASTA

>7L05_1 Tubulin alpha-1B chain (chains A, C)
MRECISIHVGQAGVQIGNACWELYCLEHGIQPDGQMPSDKTIGGGDDSFNTFFSETGAGK
HVPRAVFVDLEPTVIDEVRTGTYRQLFHPEQLITGKEDAANNYARGHYTIGKEIIDLVLD
RIRKLADQCTGLQGFLVFHSFGGGTGSGFTSLLMERLSVDYGKKSKLEFSIYPAPQVSTA
VVEPYNSILTTHTTLEHSDCAFMVDNEAIYDICRRNLDIERPTYTNLNRLISQIVSSITA
SLRFDGALNVDLTEFQTNLVPYPRIHFPLATYAPVISAEKAYHEQLSVAEITNACFEPAN
QMVKCDPRHGKYMACCLLYRGDVVPKDVNAAIATIKTKRSIQFVDWCPTGFKVGINYQPP
TVVPGGDLAKVQRAVCMLSNTTAIAEAWARLDHKFDLMYAKRAFVHWYVGEGMEEGEFSE
AREDMAALEKDYEEVGVDSVEGEGEEEGEEY

Sequence of entity 2 (B, D), FASTA

>7L05_2 Tubulin beta chain (chains B, D)
MREIVHIQAGQCGNQIGAKFWEVISDEHGIDPTGSYHGDSDLQLERINVYYNEAAGNKYV
PRAILVDLEPGTMDSVRSGPFGQIFRPDNFVFGQSGAGNNWAKGHYTEGAELVDSVLDVV
RKESESCDCLQGFQLTHSLGGGTGSGMGTLLISKIREEYPDRIMNTFSVVPSPKVSDTVV
EPYNATLSVHQLVENTDETYCIDNEALYDICFRTLKLTTPTYGDLNHLVSATMSGVTTCL
RFPGQLNADLRKLAVNMVPFPRLHFFMPGFAPLTSRGSQQYRALTVPELTQQMFDAKNMM
AACDPRHGRYLTVAAVFRGRMSMKEVDEQMLNVQNKNSSYFVEWIPNNVKTAVCDIPPRG
LKMSATFIGNSTAIQELFKRISEQFTAMFRRKAFLHWYTGEGMDEMEFTEAESNMNDLVS
EYQQYQDATADEQGEFEEEGEEDEA

Sequence of entity 3 (E), FASTA

>7L05_3 Stathmin-4 (chains E)
MADMEVIELNKCTSGQSFEVILKPPSFDGVPEFNASLPRRRDPSLEEIQKKLEAAEERRK
YQEAELLKHLAEKREHEREVIQKAIEENNNFIKMAKEKLAQKMESNKENREAHLAAMLER
LQEKDKHAEEVRKNKELKEEASRHHHHHH

Sequence of entity 4 (F), FASTA

>7L05_4 Tubulin Tyrosine Ligase (chains F)
MYTFVVRDENSSVYAEVSRLLLATGQWKRLRKDNPRFNLMLGERNRLPFGRLGHEPGLVQ
LVNYYRGADKLCRKASLVKLIKTSPELSESCTWFPESYVIYPTNLKTPVAPAQNGIRHLI
NNTRTDEREVFLAAYNRRREGREGNVWIAKSSAGAKGEGILISSEASELLDFIDEQGQVH
VIQKYLEKPLLLEPGHRKFDIRSWVLVDHLYNIYLYREGVLRTSSEPYNSANFQDKTCHL
TNHCIQKEYSKNYGRYEEGNEMFFEEFNQYLMDALNTTLENSILLQIKHIIRSCLMCIEP
AISTKHLHYQSFQLFGFDFMVDEELKVWLIEVNGAPACAQKLYAELCQGIVDVAISSVFP
LADTGQKTSQPTSIFIKLHHHHHH

Ligands and cofactors

ID	Name	Formula	Copies
CA	Calcium ion	Ca	4
MG	Magnesium ion	Mg	5
GTP	Guanosine-5'-triphosphate	C10 H16 N5 O14 P3	2
ACP	Phosphomethylphosphonic acid adenylate ester	C11 H18 N5 O12 P3	1
XQ4	(1S,2R,3S,5S,6S,16E,18E,20R,21S)-11-chloro-21-hydroxy-12,20-dimethoxy-2,5,9,16-…	C36 H51 Cl N4 O10	1
GDP	Guanosine-5'-diphosphate	C10 H15 N5 O11 P2	2

Water and common crystallization additives (EDO, CL, MES) are not listed.

Primary citation

A Biparatopic Antibody-Drug Conjugate to Treat MET-Expressing Cancers, Including Those that Are Unresponsive to MET Pathway Blockade. DaSilva, J.O., Yang, K., Surriga, O. et al. Mol Cancer Ther (2021) 20:1966-1976. DOI 10.1158/1535-7163.MCT-21-0009 · PubMed

Other PDB entries of the same protein (UniProt Q2XVP4 (AlphaFold model), which also has an AlphaFold model), best resolution first:

9U6A 1.92 Å, Tubulin-DARPin D1 in complex with a flavone
5EZY 2.05 Å, Crystal structure of T2R-TTL-taccalonolide AJ complex
5YL2 2.09 Å, Crystal structure of T2R-TTL-Y28 complex
7TTF 2.1 Å, Tubulin-RB3_SLD in complex with compound 12k
5XKG 2.2 Å, Crystal structure of T2R-TTL-CH1 complex
9M1M 2.21 Å, Cryo-EM structure of the TBC-DEC-Arl2-alpha-beta-tubulin complex with GDP-AlFx
5JQG 2.24 Å, An apo tubulin-RB-TTL complex structure used for side-by-side comparison
9M1N 2.24 Å, Cryo-EM structure of the TBC-DC-Arl2-alpha-beta-tubulin complex with GDP-AlFx
5XKH 2.25 Å, Crystal structure of T2R-TTL-CF1 complex
7TTD 2.27 Å, Tubulin-RB3_SLD in complex with compound 12e
5JCB 2.3 Å, Microtubule depolymerizing agent podophyllotoxin derivative YJTSF1
5XP3 2.3 Å, Crystal structure of apo T2R-TTL

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